bluuebunny/crossref_metadata_2025 huggingface dataset:
Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused byIFT74mutations
Authors: Fassad Mahmoud R , Rumman Nisreen , Junger Katrin , Patel Mitali P , Thompson James , Goggin Patricia , Ueffing Marius , Beyer Tina , Boldt Karsten , Lucas Jane S , Mitchison Hannah M
Published: August 2023

Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD.
A New Theoretical Model of the Right to Environment and its Practical Advantages
Authors: Chalabi Azadeh
Published: August 2023

Despite significant developments at the national, regional and international levels, to recognise the right to environment as a human right, this right is still under-theorised and contested. The challenge of giving a clear substance to such a standalone right is one that must urgently be taken up. Drawing on the NIC theory, this article develops a new model of the right to environment to serve three purposes: first, to shed light on the nature, scope and content of this right; second, to illustrate that this right can be considered as existing on three levels: individual, collective and global; and third, to explore the logical relationships between this right and already recognised human rights. This new model brings about various advantages at different levels. In particular, it allows for guiding practice for a range of actors from NGOs, human rights commissions and judges to governments and the UN human rights bodies.
Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment
Authors: Zhu Winston M , Middleton Mark R
Published: August 2023

Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour-associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy. Furthermore, there is evidence that BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the BiTE therapy blinatumomab. To overcome these inadequate T-cell responses, BiTEs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of BiTEs in solid malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination therapies and a few other less-studied combinations.
Inheritance and fitness cost of laboratory-selected resistance to Vip3Aa in Helicoverpa zea (Lepidoptera: Noctuidae)
Authors: Carrière Yves , Degain Ben , Unnithan Gopalan C , Tabashnik Bruce E
Published: August 2023

The polyphagous pest Helicoverpa zea (Lepidoptera: Noctuidae) has evolved practical resistance to transgenic corn and cotton producing Cry1 and Cry2 crystal proteins from Bacillus thuringiensis (Bt) in several regions of the United States. However, the Bt vegetative insecticidal protein Vip3Aa produced by Bt corn and cotton remains effective against this pest. To advance knowledge of resistance to Vip3Aa, we selected a strain of H. zea for resistance to Vip3Aa in the laboratory. After 28 generations of continuous selection, the resistance ratio was 267 for the selected strain (GA-R3) relative to a strain not selected with Vip3Aa (GA). Resistance was autosomal and almost completely recessive at a concentration killing all individuals from GA. Declines in resistance in heterogeneous strains containing a mixture of susceptible and resistant individuals reared in the absence of Vip3Aa indicate a fitness cost was associated with resistance. Previously reported cases of laboratory-selected resistance to Vip3Aa in lepidopteran pests often show partially or completely recessive resistance at high concentrations and fitness costs. Abundant refuges of non-Bt host plants can maximize the benefits of such costs for sustaining the efficacy of Vip3Aa against target pests.
Nonfunctional TGF-β/ALK1/ENG signaling pathway supports neutrophil proangiogenic activity in hereditary hemorrhagic telangiectasia
Authors: Duerig Inga , Pylaeva Ekaterina , Ozel Irem , Wainwright Sami , Thiel Ilona , Bordbari Sharareh , Domnich Maksim , Siakaeva Elena , Lakomek Antonia , Toppe Felicia , Schleupner Carolin , Geisthoff Urban , Lang Stephan , Droege Freya , Jablonska Jadwiga
Published: August 2023

The transforming growth factor β (TGF-β)/ALK1/ENG signaling pathway maintains quiescent state of endothelial cells, but at the same time, it regulates neutrophil functions. Importantly, mutations of this pathway lead to a rare autosomal disorder called hereditary hemorrhagic telangiectasia (HHT), characterized with abnormal blood vessel formation (angiogenesis). As neutrophils are potent regulators of angiogenesis, we investigated how disturbed TGF-β/ALK1/ENG signaling influences angiogenic properties of these cells in HHT. We could show for the first time that not only endothelial cells, but also neutrophils isolated from such patients are ENG/ALK1 deficient. This deficiency obviously stimulates proangiogenic switch of such neutrophils. Elevated proangiogenic activity of HHT neutrophils is mediated by the increased spontaneous degranulation of gelatinase granules, resulting in high release of matrix-degrading matrix metalloproteinase 9 (MMP9). In agreement, therapeutic disturbance of this process using Src tyrosine kinase inhibitors impaired proangiogenic capacity of such neutrophils. Similarly, inhibition of MMP9 activity resulted in significant impairment of neutrophil-mediated angiogenesis. All in all, deficiency in TGF-β/ALK1/ENG signaling in HHT neutrophils results in their proangiogenic activation and disease progression. Therapeutic strategies targeting neutrophil degranulation and MMP9 release and activity may serve as a potential therapeutic option for HHT.
Cytomegalovirus durably primes neutrophil oxidative burst
Authors: Marandu Thomas F , Dombek Michael , Gutknecht Michael , Griessl Marion , Riça Ingred Goretti , Vlková Barbora , Macáková Kristína , Panagioti Eleni , Griffith Alec , Lederer James , Yaffe Michael , Shankar Sidharth , Otterbein Leo , Itagaki Kiyoshi , Hauser Carl J , Cook Charles H
Published: August 2023

Cytomegalovirus (CMV) is a ubiquitous herpes virus that infects most humans, thereafter persisting lifelong in tissues of the host. It is a known pathogen in immunosuppressed patients, but its impact on immunocompetent hosts remains less understood. Recent data have shown that CMV leaves a significant and long-lasting imprint in host immunity that may confer some protection against subsequent bacterial infection. Such innate immune activation may come at a cost, however, with potential to cause immunopathology. Neutrophils are central to many models of immunopathology, and while acute CMV infection is known to influence neutrophil biology, the impact of chronic CMV infection on neutrophil function remains unreported. Using our murine model of CMV infection and latency, we show that chronic CMV causes persistent enhancement of neutrophil oxidative burst well after resolution of acute infection. Moreover, this in vivo priming of marrow neutrophils is associated with enhanced formyl peptide receptor expression, and ultimately constitutive c-Jun N-terminal kinase phosphorylation and enhanced CD14 expression in/on circulating neutrophils. Finally, we show that neutrophil priming is dependent on viral load, suggesting that naturally infected human hosts will show variability in CMV-related neutrophil priming. Altogether, these findings represent a previously unrecognized and potentially important impact of chronic CMV infection on neutrophil responsiveness in immunocompetent hosts.
Assessment of financial screening and navigation capabilities at National Cancer Institute community oncology clinics
Authors: Bell-Brown Ari , Watabayashi Kate , Delaney Debbie , Carlos Ruth C , Langer Shelby L , Unger Joseph M , Vaidya Riha R , Darke Amy K , Hershman Dawn L , Ramsey Scott D , Shankaran Veena
Published: August 2023

Background

Cancer-related financial hardship is a side effect of cancer diagnosis and treatment, and affects both patients and caregivers. Although many oncology clinics have increased financial navigation services, few have resources to proactively provide financial counseling and assistance to families affected by cancer before financial hardship occurs. As part of an ongoing randomized study testing a proactive financial navigation intervention, S1912CD, among sites of the National Cancer Institute Community Oncology Research Program (NCORP), we conducted a baseline survey to learn more about existing financial resources available to patients and caregivers.

Methods

The NCORP sites participating in the S1912CD study completed a required 10-question survey about their available financial resources and an optional 5-question survey that focused on financial screening and navigation workflow and challenges prior to starting recruitment. The proportion of NCORP sites offering financial navigation services was calculated and responses to the optional survey were reviewed to determine current screening and navigation practices and identify any challenges.

Results

Most sites (96%) reported offering financial navigation for cancer patients. Sites primarily identified patients needing financial assistance through social work evaluations (78%) or distress screening tools (76%). Sites revealed challenges in addressing financial needs at the outset and through diagnosis, including lack of proactive screening and referral to financial navigation services as well as staffing challenges.

Conclusions

Although most participating NCORP sites offer some form of financial assistance, the survey data enabled identification of gaps and challenges in providing services. Utilizing community partners to deliver comprehensive financial navigation guidance to cancer patients and caregivers may help meet needs while reducing site burden.
Robust functional ANOVA with application to additive manufacturing
Authors: Centofanti Fabio , Colosimo Bianca Maria , Grasso Marco Luigi , Menafoglio Alessandra , Palumbo Biagio , Vantini Simone
Published: August 2023

In this paper, we propose a new robust non-parametric functional analysis of variance method (RoFANOVA) that reduces the weights of outlying curves on the functional analysis of variance. It is implemented through a permutation test based on a test statistic obtained via a functional M-estimator. The performance of the RoFANOVA is demonstrated through an extensive Monte Carlo simulation study, where it is compared with some alternatives already presented in the literature, and a motivating real-case study related to the analysis of spatter ejections in an additive manufacturing process. The RoFANOVA method is implemented in the R package rofanova, available online on CRAN.
“Solidarity with the Most Oppressed Peoples of the Earth”: The Boston Chronicle and Black Internationalist Print Culture, 1945–60
Authors: Lewontin Max
Published: August 2023

This article explores transformations in the Black press during some of the most repressive years of United States and global anticommunism in the 1940s and 1950s. Centering on an examination of the editorial politics of the Boston Chronicle, a daily newspaper founded by Caribbean immigrants in the early twentieth century, it argues that Black leftist internationalism continued to be visible in print despite a repressive political climate shaping the experiences of Black journalists and activists. The Chronicle, a relatively understudied Black newspaper, offers a somewhat different perspective on the evolution of a vibrant, transnational print culture that linked Black freedom struggles in the United States with anticolonial movements in the British Caribbean, Africa, and Latin America. An examination of the Chronicle’s coverage and journalists in a period of deepening anticommunist repression reveals ongoing links between Black activists, anticolonial movements, and the organized left before the 1960s.
Nodule-specific cysteine-rich peptide 343 is required for symbiotic nitrogen fixation in Medicago truncatula
Authors: Zhang Rui , Shen Yitong , He Juanxia , Zhang Chenyan , Ma Yelin , Sun Chenghui , Song Xiaopan , Li Li , Zhang Sisi , Biró János Barnabás , Saifi Farheen , Kaló Péter , Chen Rujin
Published: August 2023

Symbiotic interactions between legumes and rhizobia lead to the development of root nodules and nitrogen fixation by differentiated bacteroids within nodules. Differentiation of the endosymbionts is reversible or terminal, determined by plant effectors. In inverted repeat lacking clade legumes, nodule-specific cysteine-rich (NCR) peptides control the terminal differentiation of bacteroids. Medicago truncatula contains ∼700 NCR-coding genes. However, the role of few NCR peptides has been demonstrated. Here, we report characterization of fast neutron 2106 (FN2106), a symbiotic nitrogen fixation defective (fix−) mutant of M. truncatula. Using a transcript-based approach, together with linkage and complementation tests, we showed that loss-of-function of NCR343 results in impaired bacteroid differentiation and/or maintenance and premature nodule senescence of the FN2106 mutant. NCR343 was specifically expressed in nodules. Subcellular localization studies showed that the functional NCR343-YFP fusion protein colocalizes with bacteroids in symbiosomes in infected nodule cells. Transcriptomic analyses identified senescence-, but not defense-related genes, as being significantly upregulated in ncr343 (FN2106) nodules. Taken together, results from our phenotypic and transcriptomic analyses of a loss-of-function ncr343 mutant demonstrate an essential role of NCR343 in bacteroid differentiation and/or maintenance required for symbiotic nitrogen fixation.
Examining the origins of observed terahertz modes from an optically pumped atomistic model protein in aqueous solution
Authors: Azizi Khatereh , Gori Matteo , Morzan Uriel , Hassanali Ali , Kurian Philip
Published: August 2023

The microscopic origins of terahertz (THz) vibrational modes in biological systems are an active and open area of current research. Recent experiments [Phys Rev X. 8, 031061 (2018)] have revealed the presence of a pronounced mode at ∼0.3 THz in fluorophore-decorated bovine serum albumin (BSA) protein in aqueous solution under nonequilibrium conditions induced by optical pumping. This result was heuristically interpreted as a collective elastic fluctuation originating from the activation of a low-frequency phonon mode. In this work, we show that the sub-THz spectroscopic response emerges in a statistically significant manner (>2σ) from such collective behavior, illustrating how photoexcitation can alter specific THz vibrational modes. We revisit the theoretical analysis with proof-of-concept molecular dynamics that introduce optical excitations into the simulations. Using information theory techniques, we show that these excitations can give rise to a multiscale response involving two optically excited chromophores (tryptophans), other amino acids in the protein, ions, and water. Our results motivate new experiments and fully nonequilibrium simulations to probe these phenomena, as well as the refinement of atomistic models of Fröhlich condensates that are fundamentally determined by nonlinear interactions in biology.
The Stroke Upper and Lower Extremity Physical Function Measures Were Supported for Score Reliability, Validity, and Administration Efficiency for Patients Poststroke
Authors: Deutscher Daniel , Kallen Michael A , Hayes Deanna , Werneke Mark W , Mioduski Jerome E , Toczylowski Theresa , Petitti Jessica M , Cook Karon F
Published: August 2023

Objective

The aims of this study were to (1) evaluate the suitability of newly developed items for calibration into 2 item banks for stroke upper extremity (SUE) and stroke lower extremity (SLE) physical function (PF) patient-reported outcome measures (PROMs) and to (2) assess score reliability and validity and PROM administration efficiency based on computerized adaptive testing (CAT).

Methods

A retrospective longitudinal study involving patients poststroke who were treated in outpatient rehabilitation clinics and responded to 28 and 25 region-specific candidate items addressing tasks related to upper or lower extremity PF, respectively, was conducted. Item response theory (IRT) model assumptions of unidimensionality, local independence, item fit, and presence of differential item functioning were evaluated. CAT-generated scores were assessed for reliability, validity, and administration efficiency, and 10-item short forms were assessed for reliability.

Results

Cohorts consisted of 2017 patients with stroke involving the upper extremity and 2107 patients with stroke involving the lower extremity (mean age [SD]: SUE = 62 [14] and SLE = 63 [14]; range = 14–89). Two solutions (SUE: 28-item; SLE: 24-item) supported unidimensionality and fit to the IRT model, with reliability estimates >0.93 for all administration modes. No items demonstrated differential item functioning. Scores discriminated among multiple patient groups in clinically logical ways, with better outcomes observed for patients who were younger, were male, had less chronicity, and had fewer comorbidities. The SUE and SLE, respectively, had 1 and 0.3% floor effects and 4.3 and 1.1% ceiling effects. Change score effect sizes were 0.5 (SUE) and 0.6 (SLE). Simulated CAT scores required an average of 6 (SUE) and 5.6 (SLE) items (median = 5).

Conclusion

The stroke upper extremity and stroke lower extremity PROM scores were reliable, valid, and efficient and had moderate change effect sizes for assessing PF as perceived by patients poststroke with upper and lower extremity impairments. Scores had negligible floor and acceptable ceiling effects. Based on these results, the stroke PROMs are suitable for research and routine clinical practice.

Impact

As IRT-based measures, these PROMs support clinical practice guideline recommendations for the use of outcome measures in neurologic physical therapy and the administration of condition-specific functional questions with low response burden for patients. The 10-item short forms offer a feasible alternative administration mode when CAT administration is not available.
Using Smartphones to Identify Momentary Characteristics of Persecutory Ideation Associated With Functional Disability
Authors: Buck Benjamin , Wingerson Mary , Tauscher Justin S , Enkema Matthew , Wang Weichen , Campbell Andrew T , Ben-Zeev Dror
Published: August 2023

Objectives

Though often a feature of schizophrenia-spectrum disorders, persecutory ideation (PI) is also common in other psychiatric disorders as well as among individuals who are otherwise healthy. Emerging technologies allow for a more thorough understanding of the momentary phenomenological characteristics that determine whether PI leads to significant distress and dysfunction. This study aims to identify the momentary phenomenological features of PI associated with distress, dysfunction, and need for clinical care.

Methods

A total of 231 individuals with at least moderate PI from 43 US states participated in a study involving 30 days of data collection using a smartphone data collection system combining ecological momentary assessment and passive sensors, wherein they reported on occurrence of PI as well as related appraisals, responses, and cooccurring states. Most (N = 120, 51.9%) participants reported never having received treatment for their PI, while 50 participants had received inpatient treatment (21.6%), and 60 (26.4%) had received outpatient care only.

Results

Individuals with greater functional disability did not differ in PI frequency but were more likely at the moment to describe threats as important to them, to ruminate about those threats, to experience distress related to them, and to change their behavior in response. Groups based on treatment-seeking patterns largely did not differ in baseline measures or momentary phenomenology of PI as assessed by self-report or passive sensors.

Conclusions

Smartphone data collection allows for granular assessment of PI-related phenomena. Functional disability is associated with differences in appraisals of and responses to PI at the moment.
Analysis of reproducibility and robustness of a renal proximal tubule microphysiological system OrganoPlate 3-lane 40 for in vitro studies of drug transport and toxicity
Authors: Sakolish Courtney , Moyer Haley L , Tsai Han-Hsuan D , Ford Lucie C , Dickey Allison N , Wright Fred A , Han Gang , Bajaj Piyush , Baltazar Maria T , Carmichael Paul L , Stanko Jason P , Ferguson Stephen S , Rusyn Ivan
Published: August 2023

Microphysiological systems are an emerging area of in vitro drug development, and their independent evaluation is important for wide adoption and use. The primary goal of this study was to test reproducibility and robustness of a renal proximal tubule microphysiological system, OrganoPlate 3-lane 40, as an in vitro model for drug transport and toxicity studies. This microfluidic model was compared with static multiwell cultures and tested using several human renal proximal tubule epithelial cell (RPTEC) types. The model was characterized in terms of the functional transport for various tubule-specific proteins, epithelial permeability of small molecules (cisplatin, tenofovir, and perfluorooctanoic acid) versus large molecules (fluorescent dextrans, 60–150 kDa), and gene expression response to a nephrotoxic xenobiotic. The advantages offered by OrganoPlate 3-lane 40 as compared with multiwell cultures are the presence of media flow, albeit intermittent, and increased throughput compared with other microfluidic models. However, OrganoPlate 3-lane 40 model appeared to offer only limited (eg, MRP-mediated transport) advantages in terms of either gene expression or functional transport when compared with the multiwell plate culture conditions. Although OrganoPlate 3-lane 40 can be used to study cellular uptake and direct toxic effects of small molecules, it may have limited utility for drug transport studies. Overall, this study offers refined experimental protocols and comprehensive comparative data on the function of RPETCs in traditional multiwell culture and microfluidic OrganoPlate 3-lane 40, information that will be invaluable for the prospective end-users of in vitro models of the human proximal tubule.
Faculty and Student Perceptions of Unauthorized Collaborations in the Preclinical Curriculum: Student or System Failure?
Authors: Chen H. Carrie , Brown Kirsten , Hernandez Yvonne M. , Martin Laura E. , Witkop Catherine T. , Aintablian Aleek , Prince Arianna , Artino Anthony R. , Kind Terry , Maggio Lauren A.
Published: August 2023

Purpose

Unauthorized collaboration among medical students, including the unauthorized provision of assistance and sharing of curricular and assessment materials, is a reported problem. While many faculty view such sharing as academic dishonesty, students do not always perceive these behaviors as problematic. With the trend toward more small-group and team-based learning and the proliferation of resource-sharing and online study aids, collaboration and sharing may have become a student norm. This multi-institutional, qualitative study examined faculty and student perceptions of and student motivations for unauthorized collaboration.

Method

Using a constructivist approach, the authors conducted scenario-prompted semistructured interviews with faculty and students in the preclinical curriculum. Participants were asked to reflect on scenarios of unauthorized collaboration and discuss their perceptions of student motivation and the influence of personal or environmental factors. The authors performed inductive thematic analysis of the interview transcripts using open and axial coding followed by abstraction and synthesis of themes.

Results

Twenty-one faculty and 16 students across 3 institutions were interviewed in 2021. There was variation in perceptions among faculty and among students, but little variation between faculty and students. Both participant groups identified the same 3 areas of tension/themes: faculty/curriculum goals vs student goals, inherent character traits vs modifiable behavioral states, and student relationships with their peer group vs their relationships with the medical education system. Student behaviors were perceived to be influenced by their environment and motivated by the desire to help peers. Participants suggested cultivating trust between students and the education system, environmental interventions, and educating students about acceptable and unacceptable behaviors to prevent unauthorized collaboration.

Conclusions

Given the various tensions and positive motivations behind unauthorized collaborations, institutions should consider explicitly preparing students to make thoughtful decisions when faced with competing priorities in addition to developing mitigation strategies that address the environment and its interactions with students.
Does Masking MCAT Scores During Admissions Increase Equity?
Authors: Arnold Michael J. , Dong Ting , Liotta Robert , Saguil Aaron A. , Durning Steven J.
Published: August 2023

Purpose

To improve admissions process equity, the Uniformed Services University masked Medical College Admission Test (MCAT) scores at or above the 51st percentile to admissions committee members. This policy was aimed at improving admissions rates for applicants in 2 priority groups: those from races and ethnicities underrepresented in medicine (URM) and those from lower socioeconomic status, represented by first-generation college (FGC) graduates.

Method

All applicants invited to interview were included: 1,624 applicants from admissions years 2014–2016 before MCAT score masking and 1,668 applicants from admissions years 2018–2020 during MCAT score masking. Logistic regression determined admissions likelihood before and during masking. Independent sample t tests compared average admissions committee scores for all applicants and for those in priority groups. Linear regression determined the weight of MCAT scores on admissions committee scores.

Results

Despite there being more priority group applicants during MCAT score masking, the admissions likelihood for an individual priority group applicant decreased during this period. URM applicants had an odds ratio of 0.513 for acceptance during MCAT score masking compared to before masking, and FGC applicants had an odds ratio of 0.695. Masking significantly reduced mean admissions committee scores, which decreased approximately twice as much for priority group applicants as for nonpriority group applicants (0.96 points vs 0.51 points). These score decreases were highest for priority group applicants with MCAT scores above the 67th percentile. Masking reduced the weight of MCAT scores; 10.9% of admissions committee score variance was explained by MCAT scores before masking and only 1.2% during masking.

Conclusions

Despite known disparities in MCAT scores with respect to race, ethnicity, and socioeconomic status, admissions decisions in this study were more equitable when MCAT scores were included. While masking MCAT scores reduced the influence of the exam in admissions decisions, it also reduced admissions rates for URM and FGC applicants.
Cost-effectiveness of upper extremity arthroplasties at orthopedic specialty hospitals
Authors: Drtil Arin A. , Poondla Revanth K. , Bockhorn Lauren N. , Dunn Warren R. , Hryc Corey F. , Laughlin Mitzi S. , Morris Brent J.
Published: August 2023

Background:

Major joint/limb reattachment procedures of upper extremities (Diagnosis-related group 483, DRG-483) are increasingly utilized, while average costs have increased yearly. This study seeks to determine the influence of volume, neighborhood demographics, and orthopedic specialization on the cost of DRG-483.

Methods:

Utilization and cost data for DRG-483 was extracted from Centers for Medicare and Medicaid Services (CMS) inpatient charge data from 2014-2018. Neighborhood demographic data was queried as USDA Rural-Urban Commuting Area codes (RUCA) from the United States 2010 census and Esri’s ArcMap software. Orthopedic specialization ratios for each hospital (OSR = Musculoskeletal discharges/Total Discharges) was utilized to compare Orthopedic Specialty Hospitals (OSH) = OSR>0.99 and Nonspecialty Hospitals (NSH) = OSR≤0.99. The cost of DRG-483 procedures and the influence of volume, hospital demographics, and orthopedic specialization was analyzed using linear regression models.

Results:

OSH performed DRG-483 procedures at lower average Medicare payments (AMP) than NSH in all years studied (P<0.001), averaging 15% saved per surgery. DRG-483 volume was weakly negatively correlated with AMP, averaging $2.95 saved per discharge. Finally, population density of hospital location was inversely proportional to DRG-483 AMP with metropolitan centers performing the procedure at the lowest cost to the CMS.

Conclusions:

CMS payments are optimized at urban orthopedic specialty hospitals. Eliminating the AMP difference for the 222,519 DRG-483 performed at NSH would have saved CMS over 480 million dollars between 2014-2018.
What’s Going on in the Hospital?: A Qualitative Study Investigating Patient Experiences of Prolonged Hospitalization After Video-assisted Thoracoscopic Surgery
Authors: Donsel Pernille O. , Missel Malene
Published: August 2023

Background:

Patients with lung cancer in “enhanced recovery after surgery” programs are offered the prospect of early hospital discharge before undergoing surgery. Little is known about what patients experience when hospitalization lasts longer than expected.

Objective:

To explore patient experiences of prolonged hospitalization in an “enhanced recovery after surgery” program following video-assisted thoracoscopic surgery lobectomy.

Methods:

Fifteen face-to-face, nonstructured interviews were conducted with patients who had undergone surgery and were hospitalized for 7 days or more.

Results:

Six themes emerged regarding experiences and coping strategies: lacking information, drawing boundaries, coping with boredom, time for existential thoughts, relying on other patients for reflection, and sufficient time to worry about the aftermath. The analysis was based on Gadamer’s philosophical hermeneutical approach and Antonovsky’s theory of sense of coherence (SOC).

Conclusions:

Patients had various strategies for coping with their situation when hospitalized for a prolonged period in an “enhanced recovery after surgery” program. Health care professionals had an important role in supporting patients’ individual coping strategies to help patients maintain a SOC.

Implications for Practice:

The findings can be used to understand how patients experience hospitalization when their trajectory deviates from standardized programs. Need for an individual approach to patients is recommended.

Foundational:

The results indicate an important role for nursing care in “enhanced recovery after surgery” programs and underscore that an individualized approach to patients can bolster coping strategies and thus a SOC.
Analysis of factors related to endometrial cancer in postmenopausal women with endometrial thickening
Authors: Ai Fangfang , Qin Xiaopei , Zhou Liane , Wang Shijun
Published: August 2023

Objective

To investigate the factors related to endometrial cancer (EC) in postmenopausal women with endometrial thickening and the value of endometrial thickness (ET) in predicting EC.

Methods

A retrospective study of 385 referrals to our department for hysteroscopic diagnostic curettage assessment was carried out. Univariate analysis and multiple logistic regression analysis were used to identify the independent contributors to the development of EC. The ability of ET to predict EC was evaluated by receiver operating characteristic curve analysis.

Results

The follow-up period from the identification of endometrial thickening to pathological confirmation of EC was from 2 weeks to 3 months. In the postmenopausal bleeding (PMB) group, a total of 47 participants’ specimens were pathologically malignant. Older age and polypoid mass-like lesions (P < 0.001) were independent factors associated with EC. The optimal critical value of ET in predicting EC was 9.5 mm, with a sensitivity and specificity of 70.21% and 70.67%, respectively. In the non-PMB group, six participants had evidence of malignant pathology, and only polypoid mass-like lesions were an independent factor associated with EC (P < 0.001).

Conclusions

For postmenopausal women with increased ET and PMB, older age, thicker ET, and polypoid mass-like lesions on transvaginal ultrasound were independent associated factors for EC. An ET greater than 9.5 mm is a threshold for predicting EC. For postmenopausal women with increased ET without PMB, the incidence of endometrial malignancy is low. If the woman has polypoid mass-like lesions on transvaginal ultrasound, she should receive further attention.
Loss of TAZ after YAP deletion severely impairs foregut development and worsens cholestatic hepatocellular injury
Authors: Gabdulkhakova Adelya , Krutsenko Yekaterina , Zhu Junjie , Liu Silvia , Poddar Minakshi , Singh Sucha , Ma Xiaochao , Nejak-Bowen Kari , Monga Satdarshan P.S. , Molina Laura M.
Published: August 2023

Background:

We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity.

Methods:

We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing.

Results:

DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.

Conclusions:

YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.
NIS2+™, an effective blood-based test for the diagnosis of at-risk nonalcoholic steatohepatitis in adults 65 years and older
Authors: Sanyal Arun J. , Magnanensi Jérémy , Majd Zouher , Rosenquist Christian , Vera Delphis M. , Almas James P. , Connelly Margery A.
Published: August 2023

Background:

Older patients are at increased risk for at-risk NASH, defined as NASH with NAFLD activity scores (NAS) ≥4 and significant fibrosis (F ≥ 2). The aim of this study was to compare the performance of 2 new blood tests, NIS4® and NIS2+™, with FIB-4, NFS, ELF™, and alanine aminotransferase (ALT) for the diagnosis of at-risk NASH in a cohort of patients aged ≥65 years.

Methods:

The clinical performance of multiple blood-based tests was assessed for their ability to detect at-risk NASH using the RESOLVE-IT diag cohort, a large population of patients with metabolic risk who were screened for potential inclusion in the RESOLVE-IT phase 3 trial.

Results:

The study cohort (n = 2053) included patients with the full histological spectrum of NAFLD, with patients having liver fibrosis stages F0–4 and NAS scores 0–8. NIS4® and NIS2+™ showed similar assay performance in patients who were <65 versus ≥65 years of age (AUROC = 0.80 vs. 0.78, p = 0.47; 0.81 vs. 0.83 p = 0.45, respectively) for the identification of at-risk NASH. In patients ≥65 (n = 410), NIS2+™ exhibited the highest AUROC compared to NIS4®, FIB-4, NFS, ELF™, and ALT (AUROC = 0.83 vs. 0.78, 0.68, 0.58, 0.69, 0.74, respectively; all p ≤ 0.0009). For NIS2+™, the sensitivity and NPV for ruling-out at-risk NASH at the 0.46 cutoff were 90.2% and 86.0%, and the specificity and PPV for ruling-in at-risk NASH at the 0.68 cutoff were81.1% and 76.3%, respectively.

Conclusions:

The clinical performance of NIS2+™ was superior for the diagnosis of at-risk NASH in patients ≥65 years of age. These data support the clinical value of this blood-based test for the diagnosis of at-risk NASH in older adults.
Histone methyltransferase KMT5C drives liver cancer progression and directs therapeutic response to PARP inhibitors
Authors: Tong Yu , Wang Fan , Li Songling , Guo Wenyun , Li Qianyu , Qian Yifei , Li Linfeng , Zhao Huifang , Zhang Yonglong , Gao Wei-Qiang , Liu Yanfeng
Published: August 2023

Background and Aims:

Epigenetic plasticity is a major challenge in cancer-targeted therapy. However, the molecular basis governing this process has not yet been clearly defined. Despite the considerable success of poly(ADP-ribose) polymerase inhibitors (PARPi) in cancer therapy, the limited response to PARPi, especially in HCC, has been a bottleneck in its clinical implications. Herein, we investigated the molecular basis of the histone methyltransferase KMT5C (lysine methyltransferase 5C) that governs PARPi sensitivity and explored a potential therapeutic strategy for enhancing PARPi efficacy.

Approach and Results:

We identified KMT5C, a trimethyltransferase of H4K20, as a targetable epigenetic factor that promoted liver tumor growth in mouse de novo MYC/Trp53

−/−
and xenograft liver tumor models. Notably, induction of KMT5C by environmental stress was crucial for DNA repair and HCC cell survival. Mechanistically, KMT5C interacted with the pivotal component of homologous recombination repair, RAD51, and promoted RAD51/RAD54 complex formation, which was essential for the activation of dsDNA breaks repair. This effect depended on the methyltransferase activity of KMT5C. We further demonstrated that the function of KMT5C in promoting HCC progression was dependent on RAD51. Importantly, either a pharmacological inhibitor (A196) or genetic inhibition of KMT5C sensitized liver cancer cells to PARPi.

Conclusions:

KMT5C played a vital role in promoting liver cancer progression by activating the DNA repair response. Our results revealed a novel therapeutic approach using the KMT5C inhibitor A196, concurrent with olaparib, as a potential HCC therapy.
Prognostic significance of acute kidney injury stage 1B in hospitalized patients with cirrhosis: A US nationwide study
Authors: Patidar Kavish R. , Cullaro Giuseppe , Naved Mobasshir A. , Kabir Shaowli , Grama Ananth , Orman Eric S. , Piano Salvatore , Allegretti Andrew S.
Published: August 2023

Understanding the prognostic significance of acute kidney injury (AKI) stage 1B [serum creatinine (sCr) ≥1.5 mg/dL] compared with stage 1A (sCr < 1.5 mg/dL) in a US population is important as it can impact initial management decisions for AKI in hospitalized cirrhosis patients. Therefore, we aimed to define outcomes associated with stage 1B in a nationwide US cohort of hospitalized cirrhosis patients with AKI. Hospitalized cirrhosis patients with AKI in the Cerner-Health-Facts database from January 2009 to September 2017 (n = 6250) were assessed for AKI stage 1 (≥1.5–2-fold increase in sCr from baseline) and were followed for 90 days for outcomes. The primary outcome was 90-day mortality; secondary outcomes were in-hospital AKI progression and AKI recovery. Competing-risk multivariable analysis was performed to determine the independent association between stage 1B, 90-day mortality (liver transplant as a competing risk), and AKI recovery (death/liver transplant as a competing risk). Multivariable logistic regression analysis was performed to determine the independent association between stage 1B and AKI progression. In all, 4654 patients with stage 1 were analyzed: 1A (44.3%) and 1B (55.7%). Stage 1B patients had a significantly higher cumulative incidence of 90-day mortality compared with stage 1A patients, 27.2% versus 19.7% (p < 0.001). In multivariable competing-risk analysis, patients with stage 1B (vs. 1A) had a higher risk for mortality at 90 days [sHR 1.52 (95% CI 1.20–1.92), p = 0.001] and decreased probability for AKI recovery [sHR 0.76 (95% CI 0.69–0.83), p < 0.001]. Furthermore, in multivariable logistic regression analysis, AKI stage 1B (vs. 1A) was independently associated with AKI progression, OR 1.42 (95% CI 1.14–1.72) (p < 0.001). AKI stage 1B patients have a significantly higher risk for 90-day mortality, AKI progression, and reduced probability of AKI recovery compared with AKI stage 1A patients. These results could guide initial management decisions for AKI in hospitalized patients with cirrhosis.
Microsurgical clipping of multiple aneurysms through the unilateral pterional approach via the extended lateral corridor (PAVEL): a case report
Authors: Khoshnevisan Alireza , Kankam Samuel B. , Farahbakhsh Farzin , Ahmadi Maryam , Shafizadeh Milad
Published: August 2023

Introduction and importance:

The application of pterional approach via the extended lateral corridor (PAVEL) for aneurysms of the distal basilar artery has been associated with significant successes. However, this approach has been rarely used to manage multiple aneurysms in patients who are not candidates for endovascular intervention.

Case presentation:

A 58-year-old male patient was referred to our neurosurgical unit with severe headache, nausea and vomiting, and neck pain. The patient had a history of hypertension but no past surgical history. A computerized tomography scan showed subarachnoid hemorrhage in the basal cisterns. Also, three-dimensional cerebral vascular imaging revealed three aneurysms involving the left middle cerebral artery, the basilar artery apex, and the left superior cerebellar artery. Due to his comorbidities and the severity of his symptoms, an endovascular intervention was not possible. The patient underwent the PAVEL approach to clip these three aneurysms. Following surgery, the patient had temporary right-sided hemiparesis and left-side ptosis, which improved 3 months after surgery.

Clinical discussion:

In this article, we present a narrated video of the intraoperative management of the three aneurysms and discussed the benefit and likely complications of this procedure.

Conclusion:

The PAVEL approach provides a single approach for multiple anterior and posterior circulation aneurysms instead of multiple procedures, thus minimizing patient postsurgical morbidity and mortality.
A rare case of SCHMID metaphyseal chondrodysplasia associated with hypothyroidism,growth hormone deficiency and celiac disease: case report
Authors: Chreitah Ahmad , Bress Fatima , Aljanati Omar , Alkilany Zeina , Mohammed Aria , Kherbek Fatima
Published: August 2023

Introduction and importance:

SCHMID metaphyseal chondrodysplasia is a rare cause of short stature with a good prognosis regarding other types of chondrodysplasia in reason of the normal integrity of the growth plate.

Case presentation:

The authors present a rare case of 4-year-2-month-old boy referred to our Unit for harmonious short stature, he had a waddling gait, subtle micromelia, and hyperlordosis, no special facies.

Clinical discussion:

The skeletal scan made the diagnosis of SCHMID metaphyseal chondrodysplasia. The first laboratory workup showed elevated thyroid stimulating hormone and anti-tissue transglutaminase immunoglobulin A. The duodenal biopsies confirmed the diagnosis of coeliac disease. Treatment of levothyroxine was initiated with a gluten-free diet .6 years later, his re-evaluation showed a low insulin-like growth factor 1 and low growth hormone peaks confirming the diagnosis of growth hormone deficiency, Growth hormone therapy was initiated with an adjusted dose of levothyroxine.

Conclusion:

Other causes of short stature should not be missed when diagnosing chondrodysplasia, and further investigations should be carried out to detect other concomitant disorders since metaphyseal chondrodysplasia is a rare cause for short stature while hypothyroidism and coeliac disease are relatively common.