bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of mechanical tension on fibroblast transcriptome profile and regulatory mechanisms of myocardial collagen turnover
Authors: Shiraishi Manabu , Suzuki Ken , Yamaguchi Atsushi
Published: March 2023

Excess deposition of extracellular matrix in the myocardium is a predictor of reduced left ventricular function. Although reducing the hemodynamic load is known to improve myocardial fibrosis, the mechanisms underlying the reversal of the fibrosis have not been elucidated. We focused on the elasticity of myocardial tissue, which is assumed to influence the fibroblast phenotype. Normal and fibrotic myocardium were cultured in 16 kPa and 64 kPa silicone gel‐coated dishes supplemented with recombinant TGFβ protein, respectively. Matrix‐degrading myocardium was cultured in 64 kPa silicone gel‐coated dishes with recombinant TGFβ protein and then in 16 kPa silicone gel‐coated dishes. Cardiac fibroblasts were cultured in this three‐part in vitro pathological models and compared. Fibroblasts differentiated into activated or matrix‐degrading types in response to the pericellular environment. Comprehensive gene expression analysis of fibroblasts in each in vitro condition showed Selenbp1 to be one of the genes responsible for regulating differentiation of fibroblasts. In vitro knockdown of Selenbp1 enhanced fibroblast activation and inhibited conversion to the matrix‐degrading form. In vivo knockdown of Selenbp1 resulted in structural changes in the left ventricle associated with progressive tissue fibrosis and left ventricular diastolic failure. Selenbp1 is involved in regulating fibroblast differentiation and appears to be one of the major molecules regulating collagen turnover in cardiac fibrosis.
Regenerative Capability of Human Nucleus Pulposus Cells in Degenerated Disc Under Hydrostatic Pressure Mimicking Physiologically Relevant Intradiscal Pressure In Vitro
Authors: Takeoka Yoshiki , Kanda Yutaro , Kang James D. , Mizuno Shuichi
Published: March 2023

Study Design.

Isolated human nucleus pulposus (hNP) cells from the degenerated intervertebral disc (IVD) were incubated under hydrostatic pressure (HP) and evaluated for regenerative potential.

Objectives.

To characterize metabolic turnover in hNP cells isolated from degenerated IVDs classified by Pfirrmann grade under physiologically relevant HP at high osmolality in vitro.

Summary of Background Data.

We demonstrated that bovine caudal nucleus pulposus cells isolated from healthy cows produced more extracellular matrix under cyclic HP followed by constant pressure (mimicking physiological intradiscal pressure in humans) than under no pressure in vitro. We assessed the effects of pressure on human degenerated cells isolated under the same regimen of pressure used for bovine cells.

Materials and Methods.

hNP cells isolated from discarded tissue classified as Pfirrmann grade 2 to 3 (n = 13: age, 46.7 ± 14.0) and grade 4 (n = 13: age, 53.0 ± 11.5) were incubated under cyclic HP at 0.2 to 0.7 MPa, 0.5 Hz for 2 days followed by constant pressure at 0.3 MPa for 1 day, repeated twice over 6 days. The gene expression and immunohistology of matrix molecules and catabolic and anticatabolic proteins were evaluated.

Results.

Aggrecan and collagen type II expression were significantly more upregulated under HP in grades 2 to 3 than in grade 4 tissues (both, P < 0.01). Linear regression analysis showed a positive correlation between matrix metalloproteinase 13 and tissue inhibitor for metalloproteinase 2 expression in grades 2 to 3, whereas a negative correlation was found in grade 4 (P < 0.05). Immunohistological staining revealed the activation of a mechanoreceptor, transient receptor potential vanilloid 4, under HP.

Conclusions.

Resident cells in mild-moderate degenerated discs classified as Pfirrmann grade 2 to 3 have the potential to promote extracellular matrix production and maintain adequate cell viability under physiological spinal loading.

Relevance.

This study explored the potential of degenerated remnant nucleus pulposus cells under a physiological environment, possibly leading to establishing strategies for IVD regeneration.
Effect of Early Postoperative Resolution of MRI Signal Intensity Changes on the Outcomes of Degenerative Cervical Myelopathy
Authors: Tozawa Keiichiro , Nagata Kosei , Ohtomo Nozomu , Ito Yusuke , Nakamoto Hideki , Kato So , Doi Toru , Taniguchi Yuki , Matsubayashi Yoshitaka , Tanaka Sakae , Oshima Yasushi
Published: March 2023

Study Design.

A retrospective cohort study.

Objective.

To investigate whether the timing of postoperative resolution of increased signal intensity (ISI) in the spinal cord is associated with surgical outcomes.

Summary of Background Data.

It remains unclear whether changes in ISI in the early postoperative period influence surgical outcomes.

Methods.

This retrospective cohort study evaluated consecutive patients undergoing surgery for degenerative cervical myelopathy at a single academic hospital between January 2012 and September 2019. These patients underwent magnetic resonance imaging (MRI) preoperatively, within two weeks postoperatively (early MRI) and after six months postoperatively (late MRI). ISI was classified as follows: grade 0, none; grade 1, light (obscure); and grade 2, intense (bright). Patients were categorized into the following three groups: those with postoperative ISI resolution at early MRI (group E) or only at the late MRI (group L) stage and those whose ISI was persistent (group P). The surgical outcomes were compared between these three groups.

Results.

We included 204 patients with complete data eligible for the analysis, and 163 of them had preoperative ISI. Postoperative ISI regression was observed in 49 (30.1%) patients. Of these 49 patients, 25 showed ISI resolution at early MRI (group E) and 24 only at late MRI (group L). All 49 were grade 1 on preoperative MRI, and this was not found to significantly impact surgical outcomes. In comparing surgical outcomes between the groups, group E had better postoperative Japanese Orthopedic Association scores and Japanese Orthopedic Association recovery rates than groups L and P. No significant differences were observed between groups L and P.

Conclusions.

Early resolution of preoperative grade 1 ISI on postoperative T2-weighted MRI may be associated with better surgical outcomes in patients with degenerative cervical myelopathy undergoing cervical spinal surgery.
Impact of Age on Overall Survival Among Children With Wilms Tumor
Authors: Qian David C. , Sykes-Martin Katherine D. , Tobillo Rachel , Ali Naba , Wynne Jacob F. , Eaton Bree R. , Paulino Arnold C. , Kalapurakal John A. , Esiashvili Natia
Published: March 2023

Objectives:

International trials have reported conflicting findings on whether the association between age and worse overall survival (OS) among children with Wilms tumor (WT) is due to age as an independent prognostic factor or the observation of more advanced disease at older ages. We sought to further elucidate this relationship using a population-based registry analysis.

Methods:

The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with WT under the age of 20. The association between age and OS was assessed using multivariable Cox proportional hazards regression.

Results:

In this study, 3463 patients (54% female) were diagnosed with WT between 1975 and 2016. More advanced stage, larger primary tumor size, lymph node involvement, disease requiring radiotherapy, and omission of surgery were associated with worse OS (P<0.05). More advanced stage, larger primary tumor size, and disease requiring radiotherapy were also associated with older age, whereas bilateral disease was associated with younger age (P<0.001). On average, each year of age conferred an incremental hazard ratio (HR) of 1.07 (95% CI, 1.01 to 1.12, P=0.018) independent of relevant covariates. The rise in adjusted OS HR was most pronounced after the transitions in diagnosis age from 2 to 3 (HRage 3–15 vs. 0–2 1.77, 95% CI, 1.11 to 2.82, P=0.016) and from 15 to 16 (HRage 16–19 vs. 3–15 2.58, 95% CI, 1.06 to 6.25, P=0.036).

Conclusions:

Diagnosis of pediatric WT at an older age was found to be independently associated with worse OS. Although additional prospective studies are warranted to examine tumor biology and other potential correlates, more aggressive treatment of older children based on age, especially as they approach early adulthood, may be considered in the multidisciplinary management of WT.
Potential Cardioprotective Role of Menaquinone-4 Against Cardiac Ischemia–reperfusion Injury
Authors: Hassan Ahmed El-Sayed , Hadhoud Shimaa , Elmahdi Essam , Elkattawy Hany A.
Published: March 2023

Myocardial infarction is among the leading causes of mortality. Menaquinone-4 (MK-4), a vitamin K2 analog, might play a role in rescuing cardiac ischemia/reperfusion (I/R) injury. This work aimed to discover the potential cardioprotective role of MK-4 against myocardial I/R injury in rats. Thirty-two rats were categorized into 3 groups: (I/R) control group: subjected to I/R protocol (received vehicle), MK-4 preconditioning group: MK-4 infusion for 20 minutes before the I/R protocol, and MK-4 postconditioning group: MK-4 infusion for 20 minutes at the start of the reperfusion phase. The hearts were placed in the Langendorff apparatus, and the left ventricular developed pressure (LVDP), heart rate (HR), + (LV dP/dt) max, − (LV dP/dt) max, and Tau were calculated. The necrotic mass was determined by staining it with nitro blue tetrazolium. Creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C- reactive protein (CRP), as well as cardiac superoxide dismutase (SOD), nitric oxide (NOx), malondialdehyde (MDA), and glutathione (GSH) levels were all evaluated. MK-4 postconditioning significantly reduced myocardial infarct size; increased LVDP, + (LV dp/dt) max, − (LV dp/dt) max, and HR; reduced Tau, CK-MB, LDH, CRP, IL-6, TNF-α, MDA, and NOx levels; and increased SOD activity, whereas no significant difference in the GSH level was detected. In conclusion, these data imply that MK-4 may protect the heart from the consequences of I/R.
National Documentation and Coding Practices of Noncompliance: The Importance of Social Determinants of Health and the Stigma of African-American Bias
Authors: Geskey Joseph M. , Kodish-Wachs Jodi , Blonsky Heather , Hohman Samuel F. , Meurer Steve
Published: March 2023

Patient records serve many purposes, one of which includes monitoring the quality of care provided that they can be analyzed through coding and documentation. Z-codes can provide additional information beyond a specific clinical disorder that may still warrant treatment. Social Determinants of Health have specific Z-codes that may help clinicians address social factors that may contribute to patients’ health care outcomes. However, there are Z-codes that specify patient noncompliance which has a pejorative connotation that may stigmatize patients and prevent clinicians from examining nonadherence from a social determinant of health perspective. A retrospective cross-sectional study was performed to examine the associations of patient and encounter characteristics with the coding of patient noncompliance. Included in the study were all patients >18 years of age who were admitted to hospitals participating in the Vizient Clinical Data Base (CDB) between January 1, 2019 and December 31, 2019. Almost 9 million US inpatients were included in the study. Of those, 6.3% had a noncompliance Z-code. Use of noncompliance Z-codes was associated with the following odds estimate ratio in decreasing order: the presence of a social determinant of health (odds ratio [OR], 4.817), African American race (OR, 2.010), Medicaid insurance (OR, 1.707), >3 chronic medical conditions (OR, 1.546), living in an economically distressed community (OR, 1.320), male gender (OR, 1.313), nonelective admission status (OR, 1.245), age <65 years (OR, 1.234). More than 1 in 15 patient hospitalizations had a noncompliance code. Factors associated with these codes are difficult, if not impossible, for patients to modify. Disproportionate representation of Africa-Americans among hospitalizations with noncompliance coding is concerning and urgently deserves further exploration to determine the degree to which it may be a product of clinician bias, especially if the term noncompliance prevents health care providers from looking into socioeconomic factors that may contribute to patient nonadherence.
Updates in management strategies of locally advanced sinonasal malignancy
Authors: Yaniv Dan , Su Shirley Y.
Published: March 2023

Purpose of review

Sinonasal tumors are a rare heterogenous group of pathologies with poor prognosis. In recent years better definition and understanding of histology, molecular classification, biological behavior and advances in therapy have resulted in improved prognosis. The purpose of this review is to give an updated summary of the recent advances in treatment, and where relevant, with references to pathology classifications.

Recent findings

Recent publications highlight the role of induction chemotherapy and advances in radiotherapy in advanced cancers. In addition, better understanding of genomics and histology specific treatment algorithms has led to more tailored treatment approaches. The role of immunotherapy and targeted therapy are yet to be explored.

This review gives an up to date summary of the advances in contemporary management strategies for locally advanced sinonasal malignancies and can serve as a guide for researchers and clinicians.
A Clinicopathologic and Molecular Characterization of Uterine Sarcomas Classified as Malignant PEComa
Authors: Anderson William J. , Dong Fei , Fletcher Christopher D.M. , Hirsch Michelle S. , Nucci Marisa R.
Published: March 2023

Perivascular epithelioid cell tumors (PEComas) are a distinctive group of mesenchymal neoplasms that demonstrate features of smooth muscle and melanocytic differentiation. Here, we present the clinicopathologic, immunohistochemical, and molecular features of 15 uterine sarcomas diagnosed as malignant PEComa. The median patient age was 56 years (range: 27 to 86 y). The median tumor size was 8.0 cm (range: 5.0 to 14.0 cm). All tumors were classified as malignant based on the presence of mitoses (15/15; 100%), necrosis (15/15; 100%), lymphovascular invasion (8/15; 53%), and high nuclear grade (13/15; 87%). Molecular analysis revealed the mammalian target of rapamycin pathway gene mutations in 7 cases (47%), including mutually exclusive variants in TSC1 (27%) and TSC2 (20%). Recurrent alterations were also identified in TP53 (53%), RB1 (30%), ATRX (33%), and BRCA2 (13%). Tumors with inactivating ATRX mutations all demonstrated loss of ATRX expression by immunohistochemistry. Loss of expression was also observed in 2 tumors without demonstrable ATRX alterations. Clinical follow-up was available for 14 patients (range: 5 to 92 mo; median: 15 mo). Five patients developed local recurrence and 9 developed metastases; 2 patients died of their disease. Our series expands the spectrum of molecular events in tumors diagnosed as malignant PEComa and further highlights the important role of targeted sequencing in tumors with focal melanocytic marker expression.
Outcome in Children Admitted to the First PICU in Malawi*
Authors: de Visser Mirjam A. , Kululanga Diana , Chikumbanje Singatiya S. , Thomson Emma , Kapalamula Tiyamike , Borgstein Eric S. , Langton Josephine , Kadzamira Precious , Njirammadzi Jenala , van Woensel Job B. M. , Bentsen Gunnar , Weir Patricia M. , Calis Job C. J.
Published: March 2023

OBJECTIVES:

Dedicated PICUs are slowly starting to emerge in sub-Saharan Africa. Establishing these units can be challenging as there is little data from this region to inform which populations and approaches should be prioritized. This study describes the characteristics and outcome of patients admitted to the first PICU in Malawi, with the aim to identify factors associated with increased mortality.

DESIGN:

Review of a prospectively constructed PICU database. Univariate analysis was used to assess associations between demographic, clinical and laboratory factors, and mortality. Univariate associations (p < 0.1) for mortality were entered in two multivariable models.

SETTING:

A recently opened PICU in a public tertiary government hospital in Blantyre, Malawi.

PATIENTS:

Children admitted to PICU between August 1, 2017, and July 31, 2019.

INTERVENTIONS:

None.

MEASUREMENT AND MAIN RESULTS:

Of 531 included PICU admissions, 149 children died (28.1%). Mortality was higher in neonates (88/167; 52.7%) than older children (61/364; 16.8%; p ≤ 0.001). On univariate analysis, gastroschisis, trachea-esophageal fistula, and sepsis had higher PICU mortality, while Wilms tumor, other neoplasms, vocal cord papilloma, and foreign body aspiration had higher survival rates compared with other conditions. On multivariable analysis, neonatal age (adjusted odds ratio [AOR], 4.0; 95% CI, 2.0–8.3), decreased mental state (AOR, 5.8; 95 CI, 2.4–13.8), post-cardiac arrest (AOR, 2.0; 95% CI, 1.0–8.0), severe hypotension (AOR, 6.3; 95% CI, 2.0–19.1), lactate greater than 5 mmol/L (AOR, 4.2; 95% CI, 1.5–11.2), pH less than 7.2 (AOR, 3.1; 95% CI, 1.2–8.0), and platelets less than 150 × 109/L (AOR, 2.4; 95% CI, 1.1–5.2) were associated with increased mortality.

CONCLUSIONS:

In the first PICU in Malawi, mortality was relatively high, especially in neonates. Surgical neonates and septic patients were identified as highly vulnerable, which stresses the importance of improvement of PICU care bundles for these groups. Several clinical and laboratory variables were associated with mortality in older children. In neonates, severe hypotension was the only clinical variable associated with increased mortality besides blood gas parameters. This stresses the importance of basic laboratory tests, especially in neonates. These data contribute to evidence-based approaches establishing and improving future PICUs in sub-Saharan Africa.
Aortic Peak Flow Velocity As a Predictor of Fluid Responsiveness in Mechanically Ventilated Children: A Systematic Review and Meta-Analysis
Authors: Sethasathien Saviga , Jariyasakoolroj Theerapon , Silvilairat Suchaya , Srisurapanont Manit
Published: March 2023

Objectives:

This meta-analysis aimed to determine the accuracy of the respiratory variations in aortic peak flow velocity (delta Vpeak) in predicting fluid responsiveness and the moderators of that accuracy.

Data Sources:

We performed searches for studies that used delta Vpeak as a predictor of fluid responsiveness in mechanically ventilated children in PubMed, Embase, Scopus, and CINAHL from inception to June 20, 2022.

Study Selection and Data Extraction:

Fifteen studies (n = 452) were included in this meta-analysis. The diagnostic test data of the included studies were synthesized as pooled sensitivity, specificity, and diagnostic odds ratio (DOR) and the area under the curve (AUC) of the summary receiver operating characteristic of delta Vpeak.

Data Synthesis:

The delta Vpeak cutoff values applied in these studies had a median of 12.3% (interquartile range, 11.50–13.25%). The pooled sensitivity and specificity of delta Vpeak were 0.80 (95% CI, 0.71–0.87) and 0.82 (95% CI, 0.75–0.87), respectively. The DOR of delta Vpeak was 23.41 (95% CI, 11.61–47.20). The AUC of delta Vpeak was 0.87. Subgroup analyses revealed that the accuracy of delta Vpeak was not moderated by ventilator settings, measures of delta Vpeak, gold standard index, the cutoff gold standard value of responders, type and volume of fluid, duration of fluid challenge, use of vasoactive drugs, general anesthesia, and cardiopulmonary bypass.

Conclusions:

By using the cutoff of approximately 12.3%, the delta Vpeak appears to have good accuracy in predicting fluid responsiveness in mechanically ventilated children. The moderators of delta Vpeak predictability are not found.
Locoregional Treatment of Glioblastoma With Targeted α Therapy
Authors: Królicki Leszek , Kunikowska Jolanta , Bruchertseifer Frank , Kuliński Radosław , Pawlak Dariusz , Koziara Henryk , Rola Rafał , Morgenstern Alfred , Merlo Adrian
Published: March 2023

Background

Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [213Bi]Bi-DOTA–substance P (SP) and [225Ac]Ac-DOTA-SP.

Methods

Treatment was performed as salvage therapy in patients with recurrent primary and secondary GB. [213Bi]Bi-DOTA-SP with injected activity 1.85 GBq per cycle was used in 20 primary (48.2 ± 11.8 years old) and in 9 secondary (38.8 ± 10.8 years old) GB patients and [225Ac]Ac-DOTA-SP in 15 primary (45.1 ± 9.9 years old) and in 6 secondary (37.8 ± 6.4 years old) GB patients with a dose escalation scheme (10, 20, and 30 MBq).

Results

Local treatment with [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP was well tolerated with only few adverse effects. There was no statistically significant difference between [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP groups in survival parameters. For primary GB, survival parameters of patients treated with [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP were as follows(in months): progression-free survival time, 2.7 versus 2.4; OS-d (overall survival from time of diagnosis to death from any cause), 23.6 versus 21.0; OS-t (overall survival from the start of treatment to death from any cause), 7.5 versus 5.0; and OS-r (overall survival from recurrence in primary tumors to death from any cause), 10.9 versus 12.0. Survival parameters of secondary GB patients treated with [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP were as follows (in months): progression-free survival time, 5.8 versus 2.4; OS-d, 52.3 versus 65.0; OS-t, 16.4 versus 16.0; and OS-c (overall survival from conversion into secondary GB multiforme to death from any cause), 18.4 versus 36.0.

Conclusions

The similarity results of 213Bi or 225Ac may suggest that the local treatment of brain tumors can be greatly simplified. The experience to date shows that local radioisotope treatment of brain tumors requires further dosimetry studies, taking into account the complexity of biological processes.
68Ga-DOTATOC PET/CT Imaging of a Muscular Solitary Fibrous Tumor
Authors: Richard Capucine , Cros Jérôme , Seban Romain-David , Champion Laurence , Hescot Ségolène
Published: March 2023

A 73-year-old woman was referred for 68Ga-DOTATOC PET/CT staging of a grade 2 pancreatic neuroendocrine tumor, which showed the primary pancreatic tumor, liver metastases, one left pleural metastasis, and high uptake in a mass of the right triceps brachii muscle. Two years before, she underwent 18F-FDG PET/CT and 111In-pentetreotide scan, respectively, with low and high uptake of each radiotracer in the triceps mass. Histopathological analysis revealed a solitary fibrous tumor. Immunohistochemistry showed no staining for SSTR-2 and SSTR-5, suggesting tumor overexpression of another somatostatin receptor. This case highlighted a potential pitfall on 68Ga-DOTATOC PET/CT.
Metabolomics Differences of the Donor Livers Between In Situ and Ex Situ Conditions During Ischemia-free Liver Transplantation
Authors: Guo Zhiyong , Zhan Liqiang , Gao Ningxin , Zhang Zhiheng , Huang Shanzhou , Wang Linhe , Zhu Caihui , Jia Zehua , Yin Meixian , Li Fangcong , Chen Shirui , Luo Tao , Liu Yao , Jia Yu , Wang Tielong , Xu Jinghong , Li Yuexin , Zhu Yifan , Chen Yichao , Yu Chuhan , Tang Yunhua , Zhao Qiang , Wang Dongping , He Xiaoshun
Published: March 2023

Background.

Ischemia-free liver transplantation (IFLT) has been innovated to avoid graft ischemia during organ procurement, preservation, and implantation. However, the metabolism activity of the donor livers between in the in situ and ex situ normothermic machine perfusion (NMP) conditions, and between standard criteria donor and extend criteria donor remains unknown.

Methods.

During IFLT, plasma samples were collected both at the portal vein and hepatic vein of the donor livers in situ during procurement and ex situ during NMP. An ultra-high performance liquid chromatography-mass spectrometry was conducted to investigate the common and distinct intraliver metabolite exchange.

Results.

Profound cysteine and methionine metabolism, and aminoacyl-tRNA biosynthesis were found in both in situ and ex situ conditions. However, obvious D-arginine and D-ornithine metabolism, arginine and proline metabolism were only found in the in situ condition. The suppressed activities of the urea cycle pathway during ex situ condition were confirmed in an RNA expression level. In addition, compared with extend criteria donor group, standard criteria donor group had more active intraliver metabolite exchange in metabonomics level. Furthermore, we found that the relative concentration of p-cresol, allocystathionine, L-prolyl-L-proline in the ex situ group was strongly correlated with peak alanine aminotransferase and aspartate aminotransferase at postoperative days 1–7.

Conclusions.

In the current study, we show the common and distinct metabolism activities during IFLT. These findings might provide insights on how to modify the design of NMP device, improve the perfusate components, and redefine the criteria of graft viability.
Sociodemographic and Geographic Variation in Access to Neuro-Ophthalmologists in the United States
Authors: Xue Katie , Feng Yilin , Tam Vicky , Lin Chun Chieh , De Lott Lindsey B. , Hamedani Ali G.
Published: March 2023

Background:

Neuro-ophthalmologists have expertise in rare and complex disorders, but the ability of patients to access neuro-ophthalmic care has not been examined at a nationwide level.

Methods:

Using the 2020 directory of all 502 members of the North American Neuro-Ophthalmology Society as a reference, we found the practice locations of 461 confirmed practicing members and converted each street address to latitude and longitude coordinates. We calculated the travel distance and time from each census tract to the nearest practice location and calculated population-weighted averages by state, region, and other prespecified factors. Choropleth maps were used to visualize the distribution of travel distances and times across the United States.

Results:

California had the most practicing neuro-ophthalmologists out of any state (50), whereas 4 states (DE, MT, SD, and WY) had none. Washington, DC and MA had the most neuro-ophthalmologists per capita. The average travel distance and time to the nearest neuro-ophthalmologists were found to be 40.90 miles and 46.50 minutes, respectively, although a large portion of western plains and mountain regions had travel times of over 120 minutes. Patients in rural areas had longer travel times than those in urban areas, and Native American patients had the longest travel times of any racial or ethnic group.

Conclusion:

The travel time to see a neuro-ophthalmologist varies widely by state, region, and rurality, with Native American patients and rural patients being disproportionately affected. By identifying the areas with the greatest travel burdens, future policies can work to alleviate these potential barriers to care.
Technological Solutions for Urinary Continence Care Delivery for Older Adults
Authors: Omotunde Muyibat , Wagg Adrian
Published: March 2023

PURPOSE:

The aim of this scoping review was to examine available evidence regarding use of technology-based continence care delivery for older adults and to identify gaps in knowledge.

METHODS:

Scoping review.

SEARCH STRATEGY:

With the help of a medical librarian, CINAHL, Cochrane Library, EMBASE, MEDLINE, ProQuest, PubMed, SCOPUS, Web of Science, and websites were searched. Search terms included technology, sensors, older adults, urinary incontinence, continence care, nursing homes, long-term care, and continence management. All literature elements except for opinion pieces and case reports written in English within the last 15 years were included. Articles not written in the English language were excluded; our search indicated that less than 6% of returned elements were written in other languages.

FINDINGS:

After duplications were removed, 2146 potential sources were identified. After exclusions, 19 results were included in the review. Review findings suggest positive effects of technology-based continence care on older adults and those involved in their care such as enhanced delivery of a successful toileting program. Information on potential harms, from either the perspective of care provider or recipient, is limited. It is important that needs of older adults and collaborative efforts are considered in the implementation of technology-based continence care. A paucity of guidelines on the use and adoption of technology-based continence care was found; additional research into uptake and sustainability is needed.

CLINICAL IMPLICATIONS:

Technological solutions, such as sensors, need to be accurate in the measurement of urine saturation levels and timely in notifying caregivers for effective delivery of continence care. Adverse consequences of incontinence, such as incontinence-associated dermatitis or urinary tract infection, may potentially be reduced or avoided with technology-based continence care delivery.
TEAD1 is crucial for developmental myelination, Remak bundles, and functional regeneration of peripheral nerves
Authors: Grove Matthew , Kim Hyukmin , Pang Shuhuan , Amaya José Paz , Hu Guoqing , Zhou Jiliang , Lemay Michel , Son Young-Jin
Published: March 2023

Previously we showed that the hippo pathway transcriptional effectors, YAP and TAZ, are essential for Schwann cells (SCs) to develop, maintain and regenerate myelin (Grove et al., 2017; Grove, Lee, Zhao, & Son, 2020). Although TEAD1 has been implicated as a partner transcription factor, the mechanisms by which it mediates YAP/TAZ regulation of SC myelination are unclear. Here, using conditional and inducible knockout mice, we show that TEAD1 is crucial for SCs to develop and regenerate myelin. It promotes myelination by both positively and negatively regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating the cholesterol biosynthetic enzymes FDPS and IDI1. We also show stage-dependent redundancy of TEAD1 and that non-myelinating SCs have a unique requirement for TEAD1 to enwrap nociceptive axons in Remak bundles. Our findings establish TEAD1 as a major partner of YAP/TAZ in developmental myelination and functional nerve regeneration and as a novel transcription factor regulating Remak bundle integrity.
Genetic influences vary by age and sex: Trajectories of the association of cholinergic system variants and theta band event related oscillations
Authors: Chorlian David B. , Meyers Jacquelyn L. , Manz Niklas , Zhang Jian , Kamarajan Chella , Pandey Ashwini , Wang Jen-Chyong , Plawecki Martin , Edenberg Howard , Goate Alison , Tischfield Jay , Porjesz Bernice
Published: March 2023

To characterize systemic changes in genetic effects on brain development, the age variation of the associations of cholinergic genetic variants and theta band event-related oscillations (EROs) was studied in a sample of 2140 adolescents and young adults, ages 12 to 25 from the COGA prospective study. The theta band EROs were elicited in visual and auditory oddball (target detection) tasks and measured by EEG recording. Associations were found to vary with age, sex, task modality (auditory or visual), and scalp locality. Seven of the twenty-one muscarinic and nicotinic cholinergic SNPs studied in the analysis, fromCHRM2, CHRNA3, CHRNA5, andCHRNB4, had significant effects on theta band EROs with considerable age spans for some sex-modality combination. No SNP-age-modality combination had significant effects in the same direction for males and females. Results suggest that nicotinic receptor associations are stronger before age 18, while muscarinic receptor associations are stronger after age 18.
Mass-immigration shapes the antibiotic resistome of wastewater treatment plants
Authors: Zhang Lanping , Adyari Bob , Hou Liyuan , Yang Xiaoyong , Gad Mahmoud , Wang Yuwen , Ma Cong , Sun Qian , Tang Qiang , Zhang Yifeng , Yu Chang-Ping , Hu Anyi
Published: March 2023

Wastewater treatment plants (WWTPs) are the hotspots for the spread of antibiotic resistance genes (ARGs) into the environment. Nevertheless, a comprehensive assessment of the city-level and short-term daily variations of ARG surveillance is still lacking in WWTPs. Here, 285 ARGs and ten mobile gene elements (MGEs) were monitored in seven WWTPs in Xiamen via high-throughput qPCR (HT-qPCR) for seven days. The average daily load of ARGs to WWTPs was about 1.21 × 1020copies/d, and a total of 1.44 × 1018copies/d was discharged to the environment across the entire city. Interestingly, no daily variations were observed in ARG richness, abundance, and community composition. Stochastic processes were the main force determining the assembly of ARG communities, with their relative importance ranked in the order of influent (INF) > effluent (EFF) > activated sludge (AS). Further analyses indicated that bacteria and ARGs from upstream treatment units played an increasingly dominant role in shaping ARG communities in AS and EFF, respectively, suggesting the importance of mass-immigration of bacteria and ARGs from the source on ARG transport in wastewater treatment units. This emphasizes the need to revise the way we mitigate ARG contamination but focus on the source of ARGs in urban wastewater.
Transposable element RNA dysregulation in mutant KRAS(G12C) 3D lung cancer spheroids
Authors: Carrillo David , Reggiardo Roman E. , Lim John , Mantalas Gary , Peddu Vikas , Kim Daniel H.
Published: March 2023

Mutant KRAS regulates transposable element (TE) RNA and interferon-stimulated gene (ISG) expression, but it remains unclear whether diverse mutations in KRAS affect different TE RNAs throughout the genome. We analyzed the transcriptomes of 3D human lung cancer spheroids that harbor KRAS(G12C) mutations to determine the landscape of TE RNAs regulated by mutant KRAS(G12C). We found that KRAS(G12C) signaling is required for the expression of LINE- and LTR-derived TE RNAs that are distinct from TE RNAs previously shown to be regulated by mutant KRAS(G12D) or KRAS(G12V). Moreover, KRAS(G12C) inhibition specifically upregulates SINE-derived TE RNAs from the youngest Alu subfamily AluY. Our results reveal that TE RNA dysregulation in KRAS-driven lung cancer cells is mutation-dependent, while also highlighting a subset of young, Alu-derived TE RNAs that are coordinately activated with innate immunity genes upon KRAS(G12C) inhibition.
Modeling the marmoset brain using embryonic stem cell-derived cerebral assembloids
Authors: Kodera Tomoki , Takeuchi Ryosuke F. , Takahashi Sara , Suzuki Keiichiro , Kassai Hidetoshi , Aiba Atsu , Shiozawa Seiji , Okano Hideyuki , Osakada Fumitaka
Published: March 2023

Studying the non-human primate (NHP) brain is required for the translation of rodent research to humans, but remains a challenge for molecular, cellular, and circuit-level analyses in the NHP brain due to the lack ofin vitroNHP brain system. Here, we report anin vitroNHP cerebral model using marmoset (Callithrix jacchus) embryonic stem cell-derived cerebral assembloids (CAs) that recapitulate inhibitory neuron migration and cortical network activity. Cortical organoids (COs) and ganglionic eminence organoids (GEOs) were induced from cjESCs and fused to generate CAs. GEO cells expressing the inhibitory neuron marker LHX6 migrated toward the cortical side of CAs. COs developed their neural activity from a synchronized pattern to an unsynchronized pattern as COs matured. CAs showed mature neural activity with an unsynchronized pattern. The marmoset assembloid system will provide anin vitroplatform for the NHP neurobiology and facilitate translation into humans in neuroscience research, regenerative medicine, and drug discovery.
Technical upgrade of an open-source liquid handler to support bacterial colony screening
Authors: del Olmo Irene , Yubero Pablo , Gómez-Luengo Álvaro , Nogales Juan , Espeso David R.
Published: March 2023

The optimization of genetically engineered biological constructs is a key step to deliver high-impact biotechnological applications. The use of high-throughput DNA assembly methods allows the construction of enough genotypic variants to successfully cover the target design space. This, however, entails extra workload for researchers during the screening stage of candidate variants. Despite the existence of commercial colony pickers, their high price excludes small research laboratories and budget-adjusted institutions from accessing such extensive screening capability. In this work we present COPICK, a technical solution to automatize colony picking in an open-source liquid handler Opentrons OT-2. COPICK relies on a mounted camera to capture images of regular Petri dishes and detect microbial colonies for automated screening. COPICK’s software can then automatically select the best colonies according to different criteria (size, color and fluorescence) and execute a protocol to pick them for further analysis. Benchmark tests performed forE. coliandP. putidacolonies delivers a raw picking performance over pickable colonies of 82% with an accuracy of 73.4% at an estimated rate of 240 colonies/h. These results validate the utility of COPICK, and highlight the importance of ongoing technical improvements in open-source laboratory equipment to support smaller research teams.
The chemical landscape of the human ribosome at 1.67 Å resolution
Authors: Faille Alexandre , Dent Kyle C. , Pellegrino Simone , Jaako Pekka , Warren Alan J
Published: March 2023

The ability of ribosomes to translate the genetic code into protein requires a finely tuned ion and solvent ecosystem. However, the lack of high-resolution structures has precluded accurate positioning of all the functional elements of the ribosome and limited our understanding of the specific role of ribosomal RNA chemical modifications in modulating ribosome function in health and disease. Here, using a new sample preparation methodology based on functionalised pristine graphene-coated grids, we solve the cryo-EM structure of the human large ribosomal subunit to a resolution of 1.67 Å. The accurate assignment of water molecules, magnesium and potassium ions in our model highlights the fundamental biological role of ribosomal RNA methylation in harnessing unconventional carbon-oxygen hydrogen bonds to establish chemical interactions with the environment and fine-tune the functional interplay with tRNA. In addition, the structures of three translational inhibitors bound to the human large ribosomal subunit at better than 2 Å resolution provide mechanistic insights into how three key druggable pockets of the ribosome are targeted and illustrate the potential of this methodology to accelerate high-throughput structure-based design of anti-cancer therapeutics.
The acetylase activity of Cdu1 regulates bacterial exit from infected cells by protectingChlamydiaeffectors from degradation
Authors: Bastidas Robert J. , Kędzior Mateusz , Davidson Robert K. , Walsh Stephen C. , Dolat Lee , Sixt Barbara S. , Pruneda Jonathan N. , Coers Jörn , Valdivia Raphael H.
Published: March 2023

Many cellular processes are regulated by ubiquitin-mediated proteasomal degradation. Pathogens can regulate eukaryotic proteolysis through the delivery of proteins with de-ubiquitinating (DUB) activities. The obligate intracellular pathogenChlamydia trachomatissecretes Cdu1 (ChlaDUB1), a dual deubiquitinase and Lys-acetyltransferase, that promotes Golgi remodeling and survival of infected host cells presumably by regulating the ubiquitination of host and bacterial proteins. Here we determined that Cdu1’s acetylase but not its DUB activity is important to protect Cdu1 from ubiquitin-mediated degradation. We further identified threeC. trachomatisproteins on the pathogen-containing vacuole (InaC, IpaM, and CTL0480) that required Cdu1‘s acetylase activity for protection from degradation and determined that Cdu1 and these Cdu1-protected proteins are required for optimal egress ofChlamydiafrom host cells. These findings highlight a non-canonical mechanism of pathogen-mediated protection of virulence factors from degradation after their delivery into host cells and the coordinated regulation of secreted effector proteins.
Dimensionality and ramping: Signatures of sentence integration in the dynamics of brains and deep language models
Authors: Desbordes Théo , Lakretz Yair , Chanoine Valérie , Oquab Maxime , Badier Jean-Michel , Trébuchon Agnès , Carron Romain , Bénar Christian-G. , Dehaene Stanislas , King Jean-Rémi
Published: March 2023

A sentence is more than the sum of its words: its meaning depends on how they combine with one another. The brain mechanisms underlying such semantic composition remain poorly understood. To shed light on the neural vector code underlying semantic composition, we introduce two hypotheses: First, the intrinsic dimensionality of the space of neural representations should increase as a sentence unfolds, paralleling the growing complexity of its semantic representation, and second, this progressive integration should be reflected in ramping and sentence-final signals. To test these predictions, we designed a dataset of closely matched normal and Jabberwocky sentences (composed of meaningless pseudo words) and displayed them to deep language models and to 11 human participants (5 men and 6 women) monitored with simultaneous magneto-encephalography and intracranial electro-encephalography. In both deep language models and electrophysiological data, we found that representational dimensionality was higher for meaningful sentences than Jabberwocky. Furthermore, multivariate decoding of normal versus Jabberwocky confirmed three dynamic patterns: (i) a phasic pattern following each word, peaking in temporal and parietal areas, (ii) a ramping pattern, characteristic of bilateral inferior and middle frontal gyri, and (iii) a sentence-final pattern in left superior frontal gyrus and right orbitofrontal cortex. These results provide a first glimpse into the neural geometry of semantic integration and constrain the search for a neural code of linguistic composition.

Significance statement

Starting from general linguistic concepts, we make two sets of predictions in neural signals evoked by reading multi-word sentences. First, the intrinsic dimensionality of the representation should grow with additional meaningful words. Second, the neural dynamics should exhibit signatures of encoding, maintaining, and resolving semantic composition. We successfully validated these hypotheses in deep Neural Language Models, artificial neural networks trained on text and performing very well on many Natural Language Processing tasks. Then, using a unique combination of magnetoencephalography and intracranial electrodes, we recorded high-resolution brain data from human participants while they read a controlled set of sentences. Time-resolved dimensionality analysis showed increasing dimensionality with meaning, and multivariate decoding allowed us to isolate the three dynamical patterns we had hypothesized.
To whom do restaurants’ preventive measures matter more during a pandemic? The moderating effects of need-for-cognition and relationship strength
Authors: Kim Heewon , Jang SooCheong (Shawn) , Gim Jaehee
Published: March 2023

Purpose

Does every customer respond in the same way to restaurants’ preventive measures (PM)? To answer this question, the purpose of the present study was to examine the moderating role of need-for-cognition (NC) and customer-restaurant relationship strength (RS) in the impact of restaurants’ PM on dine-in intentions using a trust (Study 1) and psychological discomfort (Study 2) as mediators.

Design/methodology/approach

Two studies were conducted using a 2 (PM: present vs control) × 2 (RS: strong vs weak) factorial design. NC was treated as a continuous variable in the regression model.

Findings

The results of two experimental studies showed that people with a high NC are more likely to show positive responses (higher trust and less discomfort) to restaurants’ PM when they have strong relationships with the restaurant. In contrast, people with a low NC did not show any interaction between PM and RS for trust and discomfort.

Practical implications

For restaurants targeting people with a high NC and with more returning customers than new customers, the study results suggest that safety measures should be promoted.

Originality/value

The present study expands the knowledge of customers’ reactions to restaurants’ PM by using the theoretical foundation of the ELM. The results of this study contribute to hospitality research by demonstrating the differences in customers’ thought processes according to their NC and the strength of their relationship with the restaurant.
Exploring knowledge work waste in public emergency services using the AHP algorithm
Authors: Santhiapillai Felix P. , Ratnayake R.M. Chandima
Published: March 2023

Purpose

This paper aims to explore knowledge work waste and defines the priorities for enhancing performance and productivity in policing and prosecution services (PPS), especially in the crime investigation process (CIP).

Design/methodology/approach

Using the analytic hierarchy process (AHP), a case study of a Norwegian police district is examined to identify and prioritize the most performance-vulnerable crime investigation unit, using the adapted knowledge work waste as the performance metric.

Findings

Nine waste categories and 15 subcategories are identified and understood within a two-dimensional network of managerial and operational waste adapted for the PPS. The AHP helps classify levels of priority for each knowledge work waste and orderly prioritization of crime investigation units.

Research limitations/implications

The findings have limited generalizability, as they are based on a single Norwegian police district. This warrants research on the wider applicability of the adapted waste categories and approach.

Practical implications

This study can support public managers in implementing lean thinking and identifying the most prominent wastes in a complex system. In this context, processes and operations are among the factors dominated by knowledge work and are dependent on multiple stakeholders, cross-functional activities and interdisciplinary collaboration, which is more challenging to measure systematically and quantitatively than in a manufacturing environment.

Originality/value

This study contributes to the gap in lean thinking literature by advancing the knowledge on the adaptation and application of the foundational principles of lean thinking in the PPS and CIP.