bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the COVID-19 Pandemic on Pediatric Preventive Health Care Among North Carolina Children Enrolled in Medicaid
Authors: Thakkar Pavan V , Scott Zeni , Hoffman Molly , Delarosa Jesse , Hickerson Jesse , Boutzoukas Angelique E , Benjamin Daniel K , Brookhart M Alan , Zimmerman Kanecia O , Moorthy Ganga S
Published: December 2023

Background

Children enrolled in private insurance had reduced preventive health care during the coronavirus disease 2019 (COVID-19) pandemic. However, the impact of the pandemic on children enrolled in Medicaid has been minimally described.

Methods

We used an administrative claims database from North Carolina Medicaid to evaluate the rates of well-child visits and immunization administration for children ≤14 months of age, and used a quasi-Poisson regression model to estimate the rate ratio (RR) of each outcome during the pandemic period (3/15/2020 through 3/15/2021) compared with the pre-pandemic period (3/15/2019 through 3/14/2020).

Results

We included 83 442 children during the pre-pandemic period and 96 634 children during the pandemic period. During the pre-pandemic period, 405 295 well-child visits and 715 100 immunization administrations were billed; during the pandemic period, 287 285 well-child visits and 457 144 immunization administrations were billed. The rates of well-child visits (RR 0.64; 95% CI, 0.64–0.64) and vaccine administration (RR 0.55; 95% CI, 0.55–0.55) were lower during the pandemic compared with the pre-pandemic period.

Conclusions

The rates of well-child visits and immunization administrations among North Carolina children enrolled in public insurance substantially decreased during the first year of the COVID-19 pandemic.
Association Between Hypoglycemia and the Occurrence of Early Onset Sepsis in Premature Infants
Authors: Kumar Karan R , Shah Sonam J , Fayyad Rawan M , Turla Toby M , O’Sullivan Laura M , Wallace Beatriz , Clark Reese H , Benjamin Daniel K , Greenberg Rachel G , Hornik Christoph P
Published: December 2023

Background

We examined the association between hypoglycemia and the occurrence of early onset sepsis (EOS) in premature infants admitted to the neonatal intensive care unit (NICU).

Methods

We included infants discharged from 358 NICUs between 1997 and 2020 with gestational age <34 weeks, ≥1 culture collected in the first 3 days of life, and ≥1 serum glucose value recorded on the day of or day prior to culture collection. We used multivariable logistic regression and inverse probability weighting (IPW) and constructed models for three definitions of hypoglycemia: American Academy of Pediatrics (AAP), Pediatric Endocrine Society, and a definition based on neurodevelopmental studies. We performed subgroup analysis in EOS episodes caused by Gram-negative and Gram-positive organisms.

Results

Of the 62,178 infants and 64,559 cultures that met study inclusion criteria, 739 (1%) cultures were positive. The median (25th, 75th percentile) glucose value was 75 mg/dL (50, 106) on the day of or day prior to a positive culture versus 70 mg/dL (50, 95) on the day of or day prior to a negative culture. We found that hypoglycemia was not associated with the occurrence of EOS for all organisms and Gram-positive organisms, whereas there was a small but significant association between the lower AAP glucose cutoff value and EOS due to Gram-negative organisms (logistic regression: risk difference [RD] 0.24% [95% CI, 0.01-0.47]; IPW: RD 0.22% [95% CI, 0.00-0.43]).

Conclusions

Hypoglycemia may be an early marker of EOS, particularly in episodes caused by Gram-negative organisms and when using a stricter definition of hypoglycemia.
Diagnostic Utility of Cerebrospinal Fluid White Blood Cell Components for the Identification of Bacterial Meningitis in Infants
Authors: Lamb Ashley E , Rent Sharla , Brannon Asia J , Greer Jonathan L , Ndey-Bongo Nyssa P , Cho Stephen H , Greenberg Rachel G , Benjamin Daniel K , Clark Reese H , Kumar Karan R
Published: December 2023

Background

To evaluate the diagnostic and predictive utility of cerebrospinal fluid (CSF) white blood cell (WBC) components in the diagnosis of bacterial meningitis in infants discharged from the neonatal intensive care unit (NICU).

Methods

We identified a cohort of infants discharged from a Pediatrix NICU between 1997 and 2020 who did not have an immunodeficiency, had at least 1 CSF culture collected within the first 120 days of life, and at least 1 CSF laboratory specimen obtained on the day of culture collection. We only included an infant’s first CSF culture and excluded cultures from CSF reservoirs and those growing contaminants or nonbacterial organisms. We examined the utility of CSF WBC components to diagnose or predict bacterial meningitis by calculating sensitivity, specificity, positive and negative predictive values, likelihood ratios, and area under the receiver operating curve (AUC) at different cutoff values for each parameter. We performed subgroup analysis excluding infants treated with antibiotics the day before CSF culture collection.

Results

Of the 20 756 infants that met the study inclusion criteria, 320 (2%) were diagnosed with bacterial meningitis. We found (AUC [95% CI]) CSF WBC count (0.76 [0.73–0.79]), CSF neutrophil count (0.74 [0.70–0.78]), and CSF neutrophil percent (0.71 [0.67–0.75]) had the highest predictive values for bacterial meningitis, even when excluding infants with early antibiotic administration.

Conclusions

No single clinical prediction rule had the optimal discriminatory power for predicting culture-proven bacterial meningitis, and clinicians should be cautious when interpreting CSF WBC parameters in infants with suspected meningitis.
Leveraging School Infection Data to Address Community COVID-19 Data Gaps
Authors: Moreda Eba , Al-Dhalimy Hedille , Ha Mary , Nwanaji-Enwerem Ezeji , Nguyen Anh , Pieters Keshiyena , Alan Brookhart M , Hickerson Jesse , Benjamin Daniel K , Zimmerman Kanecia O , Boutzoukas Angelique E
Published: December 2023

Background

At-home COVID-19 tests became available in the USA in April 2021 with widespread use by January 2022; however, the lack of infrastructure to report test results to public health agencies created a gap in public health data. Kindergarten through grade 12 (K-12) schools often tracked COVID-19 cases among students and staff; leveraging school data may have helped bridge data gaps.

Methods

We examined infection rates reported by school districts to ABC Science Collaborative with corresponding community rates from March 15, 2021 to June 3, 2022. We computed weekly ratios of community-to-district-reported rates (reporting ratios) across 3 study periods (spring 2021, fall 2021, and spring 2022) and estimated the difference and 95% confidence intervals (CIs) in the average reporting ratio between study periods.

Results

In spring 2021, before approval or widespread use of at-home testing, the community-reported infection rate was higher than the school-reported infection rate (reporting ratio: 1.40). In fall 2021 and spring 2022, as at-home testing rapidly increased, school-reported rates were higher than community-reported rates (reporting ratios: 0.82 and 0.66). Average reporting ratios decreased between spring 2021 and fall 2021 (−0.58, 95% CI −0.84, −0.32) and spring 2021 and spring 2022 (−0.73, 95% CI −0.96, −0.48); there was no significant change between fall 2021 and spring 2022 (−0.15, 95% CI −0.36, 0.06).

Conclusions

At-home COVID-19 testing resulted in significant data gaps; K-12 data could have supplemented community data. In future public health emergencies, reporting of school data could minimize data gaps, but requires additional resources including funding to track infections and standardized data reporting methods.
Voluntary Attrition Among Traditional Baccalaureate Nursing Students: An Integrative Review
Authors: Shaver Danielle E. , Viveiros Jennifer D.
Published: December 2023

AIM

The purpose of this review is to synthesize what is known about voluntary attrition from baccalaureate nursing education.

BACKGROUND

Understanding the reasons behind elective, voluntary attrition from nursing programs can help maximize resources and graduate more nurses into the workforce.

METHOD

An integrative review of the literature was conducted using the search strategy outlined by Whittemore and Knafl. The validated Mixed-Methods Appraisal Tool was used to assess the quality of the studies found in the search.

RESULTS

Ten studies met review criteria. Studies showed that academic and emotional underpreparedness, economic challenges, feelings of isolation, differences between perceptions of nursing and the realities of professional practice, and incongruence with learning objectives in clinical settings led to dissatisfaction.

CONCLUSION

It is important to educate the public about nursing as a rigorous college major. The realities of nursing school, feelings of acceptance, and academic preparedness must be addressed by educators.
Benefits of Using a Free Cloud-Based Electronic Health Record for Simulation in a Baccalaureate Nursing Program
Authors: Liechty Taryn
Published: December 2023

The rising cost of simulated electronic health record (EHR) software for students in a baccalaureate nursing program was risking student success. The need for faculty to decrease this financial burden on students was apparent. Simulation faculty created a free and cloud-based simulated EHR. High-fidelity features of the simulated EHR include barcode scanning capabilities and real-time diagnostic results. Students report that the simulated EHR is easy to navigate and they are particularly satisfied with the free cost. The EHR template, which can be customized for each simulated patient, and is now being used inside the classroom as an active learning strategy.
The STAMPPed Initiative for Pediatric Nurse Practitioner Students
Authors: Quinn Margaret , Mahat Ganga , Seaman Kimberly , Rawlins Latoya , Gillooly Diane
Published: December 2023

As the demand for nurse practitioners increases to meet health care needs, pathways to facilitate the transition into specialty advanced practice nursing education must be developed. The STudent Advisor/Mentorship Program for Pediatrics (STAMPPed) program was an innovative strategy established to support graduate nursing students with little to no pediatric clinical experience who demonstrated an interest in becoming pediatric nurse practitioners. The program provided structured guidance and support from experienced pediatric nursing faculty through monthly group meetings and the formulation of one-to-one student-faculty mentoring dyads. Mentees found the program to be helpful and foster supportive relationships.
Small G-Protein Rheb Gates Mammalian Target of Rapamycin Signaling to Regulate Morphine Tolerance in Mice
Authors: Wang Wenying , Ma Xiaqing , Du Wenjie , Lin Raozhou , Li Zhongping , Jiang Wei , Wang Lu-Yang , Worley Paul F. , Xu Tao
Published: December 2023

Background

Analgesic tolerance due to long-term use of morphine remains a challenge for pain management. Morphine acts on μ-opioid receptors and downstream of the phosphatidylinositol 3-kinase signaling pathway to activate the mammalian target of rapamycin (mTOR) pathway. Rheb is an important regulator of growth and cell-cycle progression in the central nervous system owing to its critical role in the activation of mTOR. The hypothesis was that signaling via the GTP-binding protein Rheb in the dorsal horn of the spinal cord is involved in morphine-induced tolerance.

Methods

Male and female wild-type C57BL/6J mice or transgenic mice (6 to 8 weeks old) were injected intrathecally with saline or morphine twice daily at 12-h intervals for 5 consecutive days to establish a tolerance model. Analgesia was assessed 60 min later using the tail-flick assay. After 5 days, the spine was harvested for Western blot or immunofluorescence analysis.

Results

Chronic morphine administration resulted in the upregulation of spinal Rheb by 4.27 ± 0.195-fold (P = 0.0036, n = 6), in turn activating mTOR by targeting rapamycin complex 1 (mTORC1). Genetic overexpression of Rheb impaired morphine analgesia, resulting in a tail-flick latency of 4.65 ± 1.10 s (P < 0.0001, n = 7) in Rheb knock-in mice compared to 10 s in control mice (10 ± 0 s). Additionally, Rheb overexpression in spinal excitatory neurons led to mTORC1 signaling overactivation. Genetic knockout of Rheb or inhibition of mTORC1 signaling by rapamycin potentiated morphine-induced tolerance (maximum possible effect, 52.60 ± 9.56% in the morphine + rapamycin group vs. 16.60 ± 8.54% in the morphine group; P < 0.0001). Moreover, activation of endogenous adenosine 5′-monophosphate-activated protein kinase inhibited Rheb upregulation and retarded the development of morphine-dependent tolerance (maximum possible effect, 39.51 ± 7.40% in morphine + metformin group vs. 15.58 ± 5.79% in morphine group; P < 0.0001).

Conclusions

This study suggests spinal Rheb as a key molecular factor for regulating mammalian target of rapamycin signaling.

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Metabolic dysfunction-associated steatotic liver disease and the heart
Authors: Driessen Stan , Francque Sven M. , Anker Stefan D. , Castro Cabezas Manuel , Grobbee Diederick E. , Tushuizen Maarten E. , Holleboom Adriaan G.
Published: December 2023

The prevalence and severity of metabolic dysfunction–associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach.
Simple Moving Average Applied to "ISO Method" CPAM Concentration Estimates: An Unexpected Result
Authors: Evans William C.
Published: December 2023

A surprisingly large amount of variance reduction has been observed when filtering International Organization for Standardization (ISO) “ISO Method” continuous particulate air monitor (CPAM) airborne radioactivity concentration estimates with a simple three-point moving average. This processing has relatively little lag relative to the amount of variance reduction obtained. The key factor producing this effect is the specific autocorrelation structure of the estimated concentrations, which are based on taking first differences of integrated-count data; this scheme results in successive count differences that contain a common count value between them. The observed variance reduction factor has also been derived analytically.
SWEEPING TECHNIQUE FOR THE REMOVAL OF EMULSIFIED SILICONE OIL DROPLETS FROM THE ANTERIOR SURFACE OF THE IRIS USING AN OPHTHALMIC ABSORPTION SPONGE
Authors: Kurihara Tomoki , Iwahashi Chiharu , Mano Fukutaro , Kusaka Shunji
Published: December 2023

Purpose:

Silicone oil (SO) tamponade is frequently used in complex vitreoretinal surgeries, and SO migration into the anterior chamber can lead to complications, such as glaucoma and corneal decompensation. A new technique is described for the efficient removal of emulsified SO droplets, which can adhere strongly to the anterior surface of the iris.

Methods:

The tip of an ophthalmic absorption sponge was cut to an approximately 1 mm × 1 mm size. Using forceps, the sponge was inserted through a 25-gauge trocar and then through a corneal paracentesis to gently scrape the surface of the iris to dislodge the adherent SO droplets, which were subsequently aspirated.

Results:

This technique efficiently and effectively dislodged and mobilized most emulsified SO droplets, thereby allowing removal through aspiration using a vitrector. Two months after surgery, the retina remained attached, the intraocular pressure decreased from 18 mm Hg to 15 mm Hg, and there were no visible SO droplets in the anterior chamber.

Conclusion:

The sweeping technique is a safe and efficient method to dislodge, mobilize, and aspirate emulsified SO droplets that are adherent to the anterior surface of the iris, thereby decreasing the risk of future SO-related complications.
Deep Anterior Lamellar Keratoplasty–Treated Keratoconic Eyes With Descemet Membrane Rupture
Authors: Peng Rongmei , Du Kaiyue , Yuan Bowei , Xiao Gege , Qu Yi , Xu Yonggen , Liu Enshuo , Hong Jing
Published: December 2023

Purpose:

The aim of this study was to evaluate the outcomes of deep anterior lamellar keratoplasty (DALK) and compare it with penetrating keratoplasty (PKP) in keratoconic eyes with Descemet membrane (DM) rupture.

Methods:

In this comparative retrospective case series, 33 keratoconic eyes with a history of hydrops underwent DALK and 27 received PKP. Baseline and postoperative visual acuity, corneal astigmatism, mean keratometry, endothelial cell density, and complication rates were measured.

Results:

The median follow-up of patients who underwent DALK was 45 months (range, 4–76 months) and that of patients who underwent PKP was 84 months (range, 4–136 months). Both procedures had comparable postoperative visual acuity, astigmatism, and mean keratometry. Significantly higher endothelial cell densities were observed in DALK than in PKP at 2, 3, and 5 years postsurgery (2043 ± 767 vs. 1165 ± 683 cell/mm2, P = 0.007, n = 12 in both groups at 2 years). Intra-DALK, 15 perforations occurred (44.12%) and 1 (2.94%) was converted to PKP. Graft rejection was diagnosed in 1 (3.03%) DALK procedure versus 8 (29.63%) PKP (P = 0.008), and other long-term complication rates were equivalent. Kaplan–Meier survival analysis also revealed a higher rejection-free survival rate for the DALK group (P = 0.012). Subgroup analysis within both groups based on the severity of preoperative DM rupture revealed no significant difference in any major 2-year outcomes.

Conclusions:

DALK showed similar beneficial visual outcome and safety but significantly better endothelial protection over PKP in eyes with keratoconus and previous hydrops. Therefore, DALK is recommended in posthydrops cases irrespective of the DM rupture severity.
Long-Term Follow-Up of Descemet Stripping Only: Data Up to 7 Years Postoperatively
Authors: Rizk Maria , Dubois Mathieu , Elahi Sina , Ghazal Wassim , Flamant Roxane , Tordjmane Ilan , Courtin Romain , Panthier Christophe , Gatinel Damien , Saad Alain
Published: December 2023

Purpose:

The aim of this study was to report long-term follow-up of eyes undergoing Descemet stripping only (DSO).

Methods:

This was a retrospective study including 26 eyes of 20 patients undergoing DSO between December 2015 and November 2022. Eligibility criteria included peripheral endothelial cell count (ECC) >1000 cells/mm2 and symptoms caused by central guttata. Patients underwent a central circular 4-mm descemetorhexis using a reverse Sinskey hook and a pair of descemetorhexis forceps using a peeling technique. Three parameters were measured before surgery and at last follow-up: best-corrected visual acuity (BCVA), central corneal thickness (CCT), and ECC measured centrally and at the periphery.

Results:

The mean age was 73 ± 9 years [52–90 years]. The average follow-up period was 23.7 ± 24.8 months [3–84]. Twenty-two eyes responded to DSO with 20 female eyes (91%) and 2 male eyes (9%). The mean postoperative BCVA improved from 0.3 ± 0.17 logMAR to 0.09 ± 0.13 logMAR (P value <0.05). The mean postoperative CCT decreased from 588 ± 41 μm to 546 ± 50 μm (P-value <0.05). The mean postoperative central ECC was 780 ± 257 cells/mm2 [484–1500]. Peripheral ECC decreased postoperatively (1837 ± 407 cells/mm2 preoperatively to 864 ± 340 cells/mm2 postoperatively, P value >0.05). Peripheral endothelial cell polymegathism was stable (average of 26.8% ± 6.8% preoperatively and 30.2% ± 14% postoperatively). Average peripheral endothelial cells polymorphism decreased postoperatively (63.1 ± 20.5% preoperatively to 33% ± 25% postoperatively, P value >0.05). Four eyes did not show improvement after DSO and underwent Descemet membrane endothelial keratoplasty surgery. There were 3 men (75%) and 1 women (25%). The preoperative trend was for nonresponders to have lower BCVA, higher CCT, more abnormal peripheral polymorphism, and polymegathism.

Conclusions:

The results of this study, with up to 7 years follow up, demonstrate the durability of DSO.
The Effects of Injury Type on Health-Related Quality of Life in Youth Athletes: A Cross-Sectional Analysis
Authors: Verma Rajiv , DeMaio Emily , Render Alexandria , Wild Jacob , Hunt Danielle , Cato Sarah , Shenvi Neeta , LaBella Cynthia , Stracciolini Andrea , Jayanthi Neeru
Published: December 2023

Objective:

The relationship between health-related quality of life (HRQoL) and injury type has not been analyzed for young athletes. We hypothesized that there would be no difference in HRQoL between injured athletes, injured nonathletes, and normative data for healthy youth (NDHY) or among athletes with acute, overuse, or concussion injuries.

Design:

Cross-sectional clinical cohort.

Setting:

Primary care sports medicine clinics at 3 academic institutions.

Participants:

Patients aged 8 to 18 years presenting with injury.

Independent Variables:

Injury type and athletic participation.

Main Outcome Measures:

Health-related quality of life measured 1 month after injury through the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric-25 v2.0 assessed pain interference, peer relationships, depression, fatigue, anxiety, and mobility. One-way analysis of variance was performed with P values of <0.05 considered significant. Concussion Learning Assessment and School Survey (CLASS) evaluated academic performance.

Results:

Three hundred fifty-seven patients (36% male), with average age of 14.2 years, completed HRQoL and CLASS surveys following injury. There were 196 overuse injuries (55%), 119 acute injuries (33%), and 42 concussions (12%). Ninety-four percent were athletes. Six percent were nonathletes; 90.5% of concussed patients reported grades worsening. Concussed athletes reported more fatigue (P = 0.008) compared with other injury types but no worse than NDHY. Athletes with overuse injuries had lower mobility (P = 0.005) than other injury types and NDHY. Patients with lower HRQoL were female, older age, or required surgery. No other domains had significant differences by injury type nor did HRQoL differ between the athletes, nonathletes, and NDHY.

Conclusions:

With the exception of injuries requiring surgery, HRQoL of injured young athletes was similar to NDHY in most domains.
Patient Safety in Nursing Homes From an Ecological Perspective: An Integrated Review
Authors: Min Deulle , Park Seungmi , Kim Suhee , Park Hye Ok
Published: December 2023

Objectives

The aims of the study were to identify the systemic factors affecting the characteristics and safety of older adults living in nursing homes and the resulting resident outcomes and to explore the relationship between them through an integrated literature review.

Methods

A literature search was conducted from April 22 to May 6, 2021, in the PubMed, Embase, Cochrane CENTRAL, CIHNAL, RISS, NDL, and KoreaMed databases. The following key words and MeSH terms were used for the search: “nursing home,” “skilled nursing facility,” “long-term care facility,” and “patient safety” or “safety.”

Results

Forty-seven qualifying articles were finally selected. Three domains were derived as personal factors, 12 as facility factors, and one as a policy factor. The interrelationships between them could result in positive or negative resident outcomes. The relationship between them was also reconstructed from an ecological perspective.

Conclusions

The results demonstrated that the safety and quality of life of older adults living in nursing homes were affected by both individual and institutional factors.
Methylated ctDNA Quantification: Noninvasive Approach to Monitoring Hepatocellular Carcinoma Burden
Authors: Angeli-Pahim Isabella , Chambers Anastasia , Duarte Sergio , Soma Daiki , Beduschi Thiago , Sahin Ilyas , Hughes Steven , Zarrinpar Ali
Published: December 2023

BACKGROUND:

Noninvasive, precision monitoring of hepatocellular carcinoma (HCC) treatment efficacy would greatly facilitate personalized therapy and improve patient outcomes. We hypothesize that quantifying methylated circulating tumor DNA (ctDNA) can be used to effectively monitor HCC burden without the need for biopsy.

STUDY DESIGN:

Blood samples were collected from 25 patients, 21 with HCC and 4 with benign liver masses, at various timepoints throughout the course of treatment at a high-volume academic medical center. Quantification of methylated ctDNA molecules assessed CpG sites on more than 550 preselected cancer-specific amplicons. The tumor methylation score (TMS) was calculated by measuring the difference between the amount of methylation in the plasma and buffy coat with a normal cutoff value of 120 or less.

RESULTS:

Among 10 patients with surgical HCC (5 surgical resections and 5 liver transplants), TMS revealed a statistically significant, rapid postoperative decline in 9. One patient who had a persistently elevated TMS on postoperative day 1 was subsequently found to have had metastatic disease. Patients in the negative control cohort all had normal-range pre- and postoperative TMS. Preoperative TMS correlated moderately with tumor burden on pathology (Spearman r = 0.54) of surgical specimens. From 11 subjects undergoing systemic therapy or Y90 radioembolization, analysis of 16 time periods demonstrated that the change in TMS (ΔTMS) was better associated with tumor progression than the change in Δalpha-fetoprotein (area under the curve 0.800 and 0.783, respectively). A composite score combining ΔTMS and Δalpha-fetoprotein further improved performance for detecting tumor progression with an area under the curve of 0.892.

CONCLUSIONS:

These findings indicate that ctDNA methylation scores can effectively evaluate changes in tumor burden without the need for tumor biopsy.
Pembrolizumab alters the tumor immune landscape in a patient with dMMR glioblastoma
Authors: Bartkowiak Todd , Brockman Asa A. , Mobley Bret C. , Harmsen Hannah , Moots Paul , Merrell Ryan , Johnson Douglas B. , Thompson Reid C. , Puduvalli Vinay K. , Ihrie Rebecca A.
Published: December 2023

Congenital DNA mismatch repair defects (dMMR), such as Lynch Syndrome, predispose patients to a variety of cancers and account for approximately 1% of glioblastoma cases. While few therapeutic options exist for glioblastoma, checkpoint blockade therapy has proven effective in dMMR tumors. Here we present a case study of a male in their 30s diagnosed with dMMR glioblastoma treated with pembrolizumab who experienced a partial response to therapy. Using a multiplex IHC analysis pipeline on archived slide specimens from tumor resections at diagnosis and after therapeutic interventions, we quantified changes in the frequency and spatial distribution of key cell populations in the tumor tissue. Notably, proliferating (KI67+) macrophages and T cells increased in frequency as did other KI67+ cells within the tumor. Therapeutic intervention remodeled the cellular spatial distribution in the tumor leading to a greater frequency of macrophage/tumor cell interactions and T cell/T cell interactions, highlighting impacts of checkpoint blockade on tumor cytoarchitecture and revealing spatial patterns that may indicate advantageous immune interactions in glioma and other solid tumors treated with these agents.

Insight

This work sheds light on the capacity of checkpoint blockade therapy to modulate the immune microenvironment in DNA mismatch repair deficient glioblastoma, highlights the utility of window-of-opportunity clinical trials in patient selection of immunomodulatory therapies, and demonstrates the feasibility and utility of mapping cellular interactions associated with therapeutic responses in gliomas and other solid tumors.

Statement regarding non-clinical trial status

We confirmed with a treating neurologist in this case that the treatment received by the individual whose samples are studied was part of routine clinical care and not a clinical trial, as the patient was previously diagnosed with Lynch syndrome (a mismatch repair deficiency). The use of pembrolizumab is recommended for treatment of tumors with high mutational burden due to mismatch repair deficiency and is currently considered standard of care for these tumors. Additionally, though the intervention and outcome are detailed in the manuscript, the focus of the manuscript is on reporting changes observed in the immune microenvironment at different points in the clinical trajectory - a retrospective analysis performed after clinical care was complete.
Utilization of Triglyceride Levels and Estimated Average Plasma Glucose Using Glycated Hemoglobin in Assessing Insulin Resistance: TyHBA1c index
Authors: de Oliveira Andrade Luís Jesuino , de Brito Luiz Felipe Moreno , de Oliveira Gabriela Correia Matos , de Oliveira Luisa Correia Matos , Vinhaes Bittencourt Alcina Maria , Baptista Gustavo Magno , Silva Catharina Peixoto , de Oliveira Luís Matos
Published: December 2023

Introduction

Insulin resistance (IR) is a metabolic disorder characterized by reduced sensitivity to the physiological effects of insulin, leading to an impaired ability of cells to take up glucose from the bloodstream. There are multiple indices available for assessing IR, however, they often rely on a single glycemic parameter at a specific moment, leaving a gap in the evaluation of IR over a certain period.

Objective

To develop a novel index for assessing IR by combining triglyceride levels and estimated glycemia through glycated hemoglobin (HBA1c).

Method

We used the fasting triglycerides and glucose levels (TyG) index formula by replacing fasting glucose with estimated average glucose calculated through HbA1c. The study included 200 laboratory samples, including fasting glucose, triglycerides, insulin, homeostasis model assessment for IR (HOMA-IR) index, TyG index, and estimated average glucose by HbA1c. The ideal cut-off value of the TyHBA1c index for estimating IR was established compared to the HOMA-IR index, and TyG index using a receiver operating characteristic (ROC) analysis. A weighted kappa test was used to estimate the diagnostic agreement between the TyHBA1c index and the HOMA-IR and Tyg index.

Results

The TyHBA1c index showed a higher correlation with the HOMA-IR index (r = 0.273, p = 0.000) compared to the TyG index (r = -0.617, p < 0.000). An association between HBA1c and the HOMA-IR index was observed (r = 0.215, p = 0.002). The ROC curve showed that the cutoff value for the TyHBA1c index to best estimate IR is Ln 4.74 (sensitivity 85.0% and specificity 95.0%) compared to the TyG index. The weighted kappa test revealed moderate agreement between the TyHBA1c index and the HOMA-IR index (k = 0.45, p = 0.006), and satisfactory agreement between the TyHBA1c index and the TyG index (k = 0.71, p = 0.009).

Conclusion

Our results demonstrated a strong association between the TyHBA1c index and TyG index, and the HOMA-IR index, suggesting that the TyHBA1c index may be more a indicator of IR, and more a tool in clinical practice for assessing IR.
STAT3 regulates the generation of astroglia in human brain organoids with high mTORC1 activity
Authors: Deb Bipan K. , Li Thomas L. , Blair John D. , Hockemeyer Dirk , Bateup Helen S.
Published: December 2023

During brain development, neural progenitor cells first produce neurons, then astrocytes and other glial cell types, which provide important trophic support and shape neuronal development and function. Intrinsic genetic programs interact with extracellular signals to control progenitor fate, resulting in temporally segregated periods of neurogenesis and gliogenesis. Animal models have implicated STAT3 as an important driver of astrogenesis; however, the signaling pathways that control glial differentiation during human brain development are less well understood. Prior work demonstrated that constitutive activation of mTORC1 signaling in human brain organoid models resulted in the precocious generation of glial-lineage cells. In this study, we tested whether mTORC1 acts via STAT3 to control astrogenesis in brain organoids. We show that knockdown of STAT3 reduces astrogenesis in wild-type organoids and in organoids with constitutively high mTORC1 signaling caused by deletion of the negative regulator TSC2. However, mTORC1 is not required for cytokine-induced activation of STAT3 and expression of the astrocytic protein GFAP. Together, these results show that mTORC1 acts through STAT3 to control astroglia production in human brain organoid models, but that mTOR signaling is dispensable for STAT3-driven astrogenesis.

Summary statement

Deb et al, use human brain organoid models to show a requirement for STAT3 downstream of mTORC1 in regulating astrogliogenesis during early human brain development.
A wearable, steerable, transcranial Low-Intensity Focused Ultrasound system
Authors: Bawiec Christopher R. , Hollender Peter J. , Ornellas Sarah B. , Schachtner Jessica N. , Dahill-Fuchel Jacob F. , Konecky Soren D. , Allen John J.B.
Published: December 2023

Abstract

Objectives

Transcranial Low-Intensity Focused Ultrasound (LIFU) offers unique opportunities for precisely neuromodulating small and/or deep targets within the human brain, which may be useful for treating psychiatric and neurological disorders. This paper presents a novel ultrasound system that delivers focused ultrasound through the forehead to anterior brain targets and evaluates its safety and usability in a volunteer study.

Methods

The ultrasound system and workflow are described, including neuronavigation, LIFU planning, and ultrasound delivery components. Its capabilities are analyzed through simulations and experiments to establish its safe steering range. A cohort of 20 healthy volunteers received a LIFU protocol aimed at the anterior medial prefrontal cortex (amPFC), using imaging and questionnaires to screen for adverse effects.

Results

Simulations and hydrophone readings agreed with less than 5% error, and the safe steering range was found to encompass a 1.8cm x 2.5cm x 2cm volume. There were no adverse effects evident on qualitative assessments, nor any signs of damage in susceptibility-weighted imaging scans. All participants tolerated the treatment well, and the users found the interface effective as the system was capable of accurately targeting the amPFC in all participants. A post hoc analysis showed that “virtual fitting” could aid in steering the beams around subjects’ sinuses.

Conclusions

The presented system was successfully used to safely deliver LIFU through the forehead to the amPFC in all volunteers, and was well-tolerated. With the capabilities validated here and positive results of the study, this technology appears well-suited to explore LIFU’s efficacy in clinical neuromodulation contexts.
“There is nothing that can prevent me from supporting her:” Men’s perspectives on their involvement and support of women’s use of topical therapy for cervical precancer treatment in Kenya
Authors: Mungo Chemtai , Adewumi Konyin , Adoyo Everlyn , Zulu Graham , Goraya Supreet Kaur , Ogollah Cirillus , Omoto Jackton , Ferrari Renée M. , Rahangdale Lisa
Published: December 2023

Purpose

Cervical cancer disproportionately impacts women in low- and middle-income countries (LMICs). The World Health Organization’s (WHO) 90/70/90 strategy aims to eliminate cervical cancer by 2030 by increasing HPV vaccination coverage to 90%, screening 70% of eligible women, and effectively treating 90% of those with abnormal results by 2030, potentially preventing 62 million deaths in LMICs. LMICs, however, struggle with limited access to cervical precancer treatment, in part due to a lack of trained professionals and weak health systems. Effective non-surgical, self-administered, which have demonstrated efficacy in high-income countries, could bridge the treatment gap in LMICs and may be more scalable and cost-effective than provider-administered therapies. To inform feasibility studies in LMICs, data are needed on the role of male partners in influencing the acceptability and uptake of self-administered topical therapies, including their support of recommended abstinence and contraception guidelines associated with these therapies.

Methods

Between November 2022 and April 2023, we conducted five focus group discussions (FGDs) with men aged 25 to 65 years in Kenya to explore their perspective and perceived support regarding their female partners using topical self-administered therapies for cervical precancer treatment. The FGDs were moderated by local qualitative research assistants and conducted in local languages, transcribed, coded, and analyzed using qualitative description.

Results

Male participants in the FGDs strongly expressed acceptance and willingness to support their wives or partners in using topical therapies for cervical precancer treatment, if available. Reported supportive behavior included permitting the use of the therapies and support of maintaining abstinence during the recommended times. Additionally, participants desired male involvement in clinic and community-based education about topical therapies to facilitate widespread support.

Conclusion

The use of self-administered topical therapies for cervical precancer treatment, if supported by efficacy studies in LMICs, may support achieving the WHO’s 2030 goal of 90% treatment access. We find that with adequate education, men express overwhelming support of their female partner’s use of topical therapies, including adherence to abstinence and contraception guidelines.
Characterization of the distribution and dynamics of chromatin states in theC. elegansgermline reveals substantial H3K4me3 remodeling during oogenesis
Authors: Mazzetto Mariateresa , Gonzalez Lauren E. , Sanchez Nancy , Reinke Valerie
Published: December 2023

Chromatin organization in theC. elegansgermline is tightly regulated and critical for germ cell differentiation. Although certain germline epigenetic regulatory mechanisms have been identified, how they influence chromatin structure and ultimately gene expression remains unclear, in part because most genomic studies have focused on data collected from intact worms comprising both somatic and germline tissues. We therefore analyzed histone modification and chromatin accessibility data from isolated germ nuclei representing undifferentiated proliferating and meiosis I populations to define chromatin states. We correlated these states with overall transcript abundance, spatiotemporal expression patterns, and the function of small RNA pathways. Because the essential role of the germline is to transmit genetic information and establish gene expression in the early embryo, we compared epigenetic and transcriptomic profiles from undifferentiated germ cells to those of embryos to define the epigenetic changes during this developmental transition. The active histone modification H3K4me3 shows particularly dynamic remodeling as germ cells differentiate into oocytes, which suggests a mechanism for establishing early transcription of essential genes during zygotic genome activation. This analysis highlights the dynamism of the chromatin landscape across developmental transitions and provides a resource for future investigation into epigenetic regulatory mechanisms in germ cells.
Role of behind-the-border factors in determining state-level differences in FDI inflows to India
Authors: Prabhakar Prerna , Aggarwal Muskan
Published: December 2023

Purpose

Although India is seen as a key player in the global economy, it is still below its potential level of growth. In this age of globalism, integration with the global economy through trade and foreign investments fosters domestic growth. For India, although this integration has strengthened over the years, there are certain gaps that remain to be addressed. Though numerous studies in the literature have tried to find answers to these questions, an important aspect that has not been considered by these studies relates to India’s federal structure and the role of states in determining the aggregate economic outcome. As Foreign Direct Investment (FDI) inflows to India are concentrated in a few states, this paper aims to provide an assessment of the reasons behind this trend.

Design/methodology/approach

This paper aims to investigate the reasons behind the interstate differences with respect to FDI inflows in India. The analytical work undertaken for this paper is based on secondary data, collected and collated from various sources. The approach adopted for this paper includes a heat graph analysis to examine whether there is a clear pattern in terms of the state-specific factors for high FDI states versus the low FDI states. This data analysis is followed by an econometric estimation to gauge the impact of state-specific factors in determining the FDI inflows.

Findings

As per the secondary data–driven heat graph and econometric analysis, factors like industrial output, social sector expenditure, judicial quality, connectivity indicators, labor cost and availability of credit, act as differentiators between high and low FDI-receiving states. It then becomes imperative to bridge the gap between the two sets of states in terms of these specific factors. Implementation and success of policy interventions can only be derived at the state level and therefore needs more decentralized approach.

Originality/value

This paper tries to identify the reasons that are responsible for FDI inflows being concentrated in a few Indian states. This involves a comprehensive analysis of several variables to understand whether there is a clear pattern where high-FDI states are also in a better position with respect to these attributes. This effort to factor in the federal aspect of a macroeconomic indicator like FDI provides new dynamic to this area of work.
Artefacts as boundary objects for concept development: a configurational approach
Authors: Zasa Federico Paolo , Buganza Tommaso
Published: December 2023

Purpose

This study aims to investigate how configurations of boundary objects (BOs) support innovation teams in developing innovative product concepts. Specifically, it explores the effectiveness of different artefact configurations in facilitating collaboration and bridging knowledge boundaries during the concept development process.

Design/methodology/approach

The research is based on data from ten undergraduate innovation teams working with an industry partner in a creative industry. Six categories of BOs are identified, which serve as tools for collaboration. The study applies fsQCA (fuzzy-set qualitative comparative analysis) to analyse the configurations employed by the teams to bridge knowledge boundaries and support the development of innovative product concepts.

Findings

The findings of the study reveal two distinct groups of configurations: product envisioning and product design. The configurations within the “product envisioning” group support the activities of visioning and pivoting, enabling teams to innovate the product concept by altering the product vision. On the other hand, the configurations within the “product design” group facilitate experimenting, modelling and prototyping, allowing teams to design the attributes of the innovative product concept while maintaining the product vision.

Originality/value

This research contributes to the field of innovation by providing insights into the role of BOs and their configurations in supporting innovation teams during concept development. The results suggest that configurations of “product envisioning” support bridging semantic knowledge boundaries, while configurations within “product design” bridge pragmatic knowledge boundaries. This understanding contributes to the broader field of knowledge integration and innovation in design contexts.
Rethinking innovation through industry and society 5.0 paradigms: a multileveled approach for management and policy-making
Authors: Troisi Orlando , Visvizi Anna , Grimaldi Mara
Published: December 2023

Purpose

Industry 4.0 defines the application of digital technologies on business infrastructure and processes. With the increasing need to take into account the social and environmental impact of technologies, the concept of Society 5.0 has been proposed to restore the centrality of humans in the proper utilization of technology for the exploitation of innovation opportunities. Despite the identification of humans, resilience and sustainability as the key dimensions of Society 5.0, the definition of the key factors that can enable Innovation in the light of 5.0 principles has not been yet assessed.

Design/methodology/approach

An SLR, followed by a content analysis of results and a clustering of the main topics, is performed to (1) identify the key domains and dimensions of the Industry 5.0 paradigm; (2) understand their impact on Innovation 5.0; (3) discuss and reflect on the resulting implications for research, managerial practices and the policy-making process.

Findings

The findings allow the elaboration of a multileveled framework to redefine Innovation through the 5.0 paradigm by advancing the need to integrate ICT and technology (Industry 5.0) with the human-centric, social and knowledge-based dimensions (Society 5.0).

Originality/value

The study detects guidelines for managers, entrepreneurs and policy-makers in the adoption of effective strategies to promote human resources and knowledge management for the attainment of multiple innovation outcomes (from technological to data-driven and societal innovation).