bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep and insulin sensitivity in adolescents at risk of type 2 diabetes: the Sleep Manipulation in Adolescents at Risk of Type 2 Diabetes randomized crossover study
Authors: Dutil Caroline , Podinic Irina , Featherstone Ryan B , Eaton Amelia , Sadler Christin M , Goldfield Gary S , Hadjiyannakis Stasia , Gruber Reut , Tremblay Mark S , Prud’homme Denis , Chaput Jean-Philippe
Published: December 2023

Study Objectives

To investigate the effect of increasing sleep duration for 1 week, compared to a week of habitual and decreased sleep, on insulin sensitivity (IS) in adolescents at risk for type 2 diabetes (T2D).

Methods

Adolescents, 13–18 years old, at risk for T2D, with obesity and other risk factors, were recruited for a randomized (1:1), open-label, sex-stratified crossover study, that manipulated time-in-bed to modify sleep duration (measured by actigraphy). Following a week of habitual (HB) sleep, time-in-bed was increased (IN) and decreased (DE) by 1 hour 30 min/night for 1 week, counterbalanced across participants (HBINDE or HBDEIN), and separated by a week of washout sleep. The main outcome measure was IS, obtained via 2-hour oral-glucose-tolerance-test conducted after each sleep week.

Results

Of the 43 participants recruited, 36 (84%) completed all sleep interventions (52.8% female, age = 15.1 years, body mass index = 99.9th percentile, order: HBINDE = 18 and HBDEIN = 18). On average, during the HB week, participants slept 7 hours 31 min/night; sleep duration was 1 hour 02 min/night higher during the IN week and 1 hour 19 min/night lower during the DE week. We found a significant effect of sleep week on IS with a large effect size. Following the IN sleep week, IS was 20% higher compared to after the HB and DE sleep weeks, but there was no significant difference in IS following HB versus DE sleep weeks.

Conclusions

Whenever possible, clinicians should empower youth at risk of T2D to improve their sleep duration, since even a modest increase in sleep duration of 1 h/night for 1 week can have a positive impact on IS in this population.

Clinical Trials

Sleep Extension and IS in Adolescents, https://clinicaltrials.gov/study/NCT03754036, November 23rd, 2018.

Trial registration

ClinicalTrials.gov (ID:NCT03754036).
Evaluation of the new poisoning mortality score in comparison with PSS and SOFA scoring systems to predict mortality in poisoned patients admitted to the intensive care unit
Authors: Saeed Sara , Elmorsy Sarah Ahmad
Published: December 2023

Objective

Mortality prediction in acute poisoning patients aids in prompt and effective treatment. This study aimed to evaluate the effectiveness of the new Poisoning Mortality Score (PMS) in comparison with the Poison Severity Score (PSS) and Sequential Organ Failure Assessment (SOFA) scoring systems in poisoned patients admitted to the intensive care unit (ICU).

Material and Methods

The medical records of 523 poisoned patients admitted to the ICU of the Poison Control Centre from September 2021 to June 2022 were examined retrospectively. The PMS, PSS, and SOFA scores were calculated based on the worst values of the first 24 h of admission.

Results

A total of 100 patients were enrolled in the study, and the in-hospital mortality rate was 28%. The best cut-off points for predicting mortality for PMS, PSS, and SOFA scores were > 53, > 2, and > 6, with sensitivities of 67.9%, 85.7%, and 82.4% and specificities of 73.6%, 84.7%, and 83.3% respectively. In a pairwise comparison of the AUCs for PMS, PSS, and SOFA scores, SOFA displayed significantly greater accuracy than PSS and PMS.

Conclusion

The PMS, PSS, and SOFA scoring systems were significant predictors of mortality in ICU-admitted poisoned patients, however, the SOFA score showed the best performance (OR = 1.77, and 95% CI = 1.42-2.54) with significant P-value (0.002) as a predictor of mortality and highest AUC(0.904).
Zoledronic acid and ibandronate-induced nephrotoxicity in 2D and 3D proximal tubule cells derived from human and rat
Authors: Valencia Leslie J , Tseng Min , Chu Mei-Lan , Yu Lanlan , Adedeji Adeyemi O , Kiyota Tomomi
Published: December 2023

Drug-induced proximal tubule (PT) injury remains a serious safety concern throughout drug development. Traditional in vitro 2-dimensional (2D) and preclinical in vivo models often fail to predict drug-related injuries presented in clinical trials. Various 3-dimensional (3D) microphysiological systems (MPSs) have been developed to mimic physiologically relevant properties, enabling them to be more predictive toward nephrotoxicity. To explore the capabilities of an MPS across species, we compared cytotoxicity in hRPTEC/TERT1s and rat primary proximal tubular epithelial cells (rPPTECs) following exposure to zoledronic acid and ibandronate (62.5–500 µM), and antibiotic polymyxin B (PMB) (50 and 250 µM, respectively). For comparison, we investigated cytotoxicity using 2D cultured hRPTEC/TERT1s and rPPTECs following exposure to the same drugs, including overlapping concentrations, as their 3D counterparts. Regardless of the in vitro model, bisphosphonate-exposed rPPTECs exhibited cytotoxicity quicker than hRPTEC/TERT1s. PMB was less sensitive toward nephrotoxicity in rPPTECs than hRPTEC/TERT1s, demonstrating differences in species sensitivity within both 3D and 2D models. Generally, 2D cultured cells experienced faster drug-induced cytotoxicity compared to the MPSs, suggesting that MPSs can be advantageous for longer-term drug-exposure studies, if warranted. Furthermore, ibandronate-exposed hRPTEC/TERT1s and rPPTECs produced higher levels of inflammatory and kidney injury biomarkers compared to zoledronic acid, indicating that ibandronate induces acute kidney injury, but also a potential protective response since ibandronate is less toxic than zoledronic acid. Our study suggests that the MPS model can be used for preclinical screening of compounds prior to animal studies and human clinical trials.
Prolongation of the Menstrual Cycle After Receipt of the Primary Series and Booster Doses of mRNA Coronavirus Disease 2019 (COVID-19) Vaccination
Authors: Hosoya Satoshi , Piedvache Aurelie , Nakamura Akari , Nasu Risa , Hine Maaya , Itoi Shiori , Yokomizo Ryo , Umezawa Akihiro , Hiraike Osamu , Koga Kaori , Osuga Yutaka , Narumi Satoshi , Morisaki Naho
Published: December 2023

OBJECTIVE:

To quantitatively evaluate the effect of a booster vaccination dose against coronavirus disease 2019 (COVID-19) on menstrual cycle in a large-scale retrospective cohort study using a menstrual cycle tracking smartphone application (app).

METHODS:

Prospectively or retrospectively recorded data, including the start and finish dates of menstrual cycles, were collected with the app. Detailed data on vaccinations, side effects, and participants' characteristics were retrospectively collected from a questionnaire on the app. For each COVID-19 vaccination shot (first, second, and third), within-individual changes in menstrual cycle length up to the fourth postvaccination cycle were evaluated.

RESULTS:

Among the 7,376 and 6,873 participants who had the first and second COVID-19 vaccine doses in different menstrual cycles, respectively, menstrual cycles immediately after the vaccination (first postvaccination cycles) were an average of 0.22 days (95% CI, 0.06–0.39) and 0.37 days (95% CI, 0.20–0.54) longer than the prevaccination cycle. In contrast, among the 1,672 participants who received the first and second doses in the same cycle, the first postvaccination cycle was an average of 4.21 days (95% CI, 3.69–4.72) longer. The second to fourth postvaccination cycles returned to the level of the prevaccination cycle. However, among the 4,768 participants who had the third COVID-19 vaccine dose, the menstrual cycle immediately after the vaccination was an average of 1.20 days (95% CI, 1.00–1.40) longer, with prolongation of cycles of 0.27 days (95% CI, 0.10–0.44) to 0.41 days (95% CI, 0.22–0.59) persisting from the second to the fourth postvaccination cycle.

CONCLUSION:

The booster shot against COVID-19 may have a greater and longer-lasting effect on menstrual cycles than the primary-series shots. Although the effect size was small, evidence on the side effects of immunization on menstruation should be accumulated.
Characteristics Associated With Surgical Failure After Native Tissue Apical Prolapse Repair
Authors: Rahn David D. , Richter Holly E. , Sung Vivian W. , Hynan Linda S. , Pruszynski Jessica E.
Published: December 2023

OBJECTIVE:

To identify clinical and demographic characteristics associated with prolapse recurrence by 12 months after native tissue transvaginal repair.

METHODS:

This was a planned secondary analysis of a randomized trial including postmenopausal participants with stage 2 or greater apical or anterior vaginal prolapse scheduled for surgical repair at three U.S. sites. Participants underwent vaginal hysterectomy (if uterus was present) and standardized uterosacral or sacrospinous ligament suspension at the surgeon's discretion. The intervention was perioperative (5 weeks or more preoperatively and 12 months postoperatively) vaginal estrogen compared with placebo cream. The primary outcome was time to failure by 12 months after surgery, defined by objective prolapse of the anterior or posterior walls beyond the hymen or the apex descending more than one-third of the vaginal length, symptomatic vaginal bulge, or retreatment. For this analysis, participants were grouped according to failure compared with success, and multiple factors were compared, including age, time since menopause, race and ethnicity, parity, body mass index (BMI), baseline genital hiatus measurement, prolapse stage and point of maximal prolapse, surgery type (uterosacral or sacrospinous ligament suspension), and concomitant procedures. Factors were assessed for association with the hazard of surgical failure using Cox proportional hazards models, adjusted for site and treatment group. Factors with P<.50 from this analysis were considered for inclusion in the final multivariable model; site and treatment group were kept in this model.

RESULTS:

One hundred eighty-six participants underwent surgery; 183 provided complete data. There were 30 failures (16.4%) and 153 successes (83.4%) at 12 months. On bivariate analysis, failure was associated with decreasing age, shorter duration since menopause, Latina ethnicity, and greater baseline genital hiatus. In the final multivariable model, which included age, BMI, and point of maximal prolapse, only age remained significantly associated with surgical failure (adjusted hazard ratio [per year] 0.92, 95% CI, 0.86–0.98, P=.016).

CONCLUSION:

Among postmenopausal women, younger age was associated with increased frequency of prolapse recurrence by 12 months after native tissue repair.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT02431897.
Is Ultrasound-guided or Landmark-guided Intra-articular Lidocaine Injection More Effective for Pain Control in Anterior Shoulder Dislocation Reduction? A Randomized Controlled Trial
Authors: Rungsinaporn Visit , Innarkgool Sirasit , Kongmalai Pinkawas
Published: December 2023

Background

Effective pain control during reduction of shoulder dislocation is essential for patient comfort. However, there is a lack of comprehensive research comparing the efficacy of different pain management techniques, specifically landmark-guided and ultrasound-guided intra-articular analgesic injections.

Questions/purposes

Among patients undergoing closed reduction of a shoulder dislocation, were there differences between an intra-articular shoulder injection placed using anatomic landmarks and an ultrasound-guided intra-articular injection in terms of (1) pain before versus after the injection and pain before injection versus after the reduction, or (2) length of stay in the emergency department and complications of the procedure?

Methods

Between August 2021 and March 2023, 28 patients with anterior shoulder dislocation were treated at the emergency department of a tertiary referral care center. They were randomly assigned to either the landmark-guided or ultrasound-guided intra-articular lidocaine injection group. Differences in pain levels between preinjection and postinjection, preinjection and postreduction, length of hospital stay, and complications were assessed and compared between the two groups. Patients were followed for 2 weeks.

Results

There were no between-group differences in terms of age, gender, baseline pain score, and any other relevant factors. There were no differences between the groups in terms of pain reduction between preinjection and postinjection (landmark-guided: ΔVAS 2.8 ± 1.1, ultrasound-guided: ΔVAS 2.9 ± 1.0, mean difference -0.14 [95% confidence interval -0.97 to 0.68]; p = 0.72) or between preinjection and postreduction (landmark-guided: ΔVAS 6.6 ± 2.1, ultrasound-guided: ΔVAS 5.8 ± 1.8, mean difference 0.79 [95% CI -0.74 to 2.31]; p = 0.30). There were no differences in length of stay in the emergency department (landmark-guided: 162 ± 38 minutes, ultrasound-guided: 184 ± 73 minutes, mean difference 22 minutes [95% CI -67 to 24]; p = 0.33), and no complications were reported in either group during the 2-week follow-up period.

Conclusion

The results of the landmark-guided technique were not different from those of ultrasound-guided injection in terms of lower pain levels, length of stay, and complications. These findings provide valuable guidance for orthopaedic surgeons, enabling them to make informed decisions based on their expertise and available resources.

Level of Evidence

Level I, therapeutic study.
Primary Mucinous Carcinoma of Skin: A Rare Cutaneous Neoplasm. Clinicopathologic Features, Differential Diagnoses, and Review of Literature
Authors: Tinguria Mukund
Published: December 2023

Primary mucinous carcinoma of the skin (PMCS) is a rare malignant neoplasm of sweat gland origin, with an incidence of 0.07 per million. Histologically, it may be difficult to differentiate it from metastatic mucinous carcinomas of the skin. A case of PMCS is reported here in a 59-year-old woman who presented with a lesion on the right lower eyelid. Histological examination revealed features of mucinous adenocarcinoma. The main differential diagnosis was metastatic mucinous adenocarcinoma; however, the lack of colorectal and lung markers and the presence of focal in situ components were consistent with the diagnosis of PMCS. PMCS and breast mucinous carcinoma share immunohistochemical markers, such as GCDFP-15 and mammaglobin; however, focal in situ component with the presence of myoepithelial cells in the tumor ruled out metastatic mucinous carcinoma of breast origin. The subsequent mammograms did not reveal any breast lesions. Colonoscopy did not show any evidence of colonic malignancy, and imaging studies (CT scan) did not show any evidence of neoplasm in the body. These findings were in keeping with a diagnosis of PMCS. The present case emphasizes the importance of clinicopathological correlation, histopathology, and immunohistochemistry in the accurate diagnosis of PMCS and summarizes the literature on these rare cutaneous neoplasms.
The Impact of Nursing Education on Ventilator-Associated Pneumonia Prevention Bundle to Reduce Incidence of Infection: A Quality Improvement Project
Authors: Alfano Aubrey , Riddle Katie , Nordstrom Kyle , Buterakos Roxanne , Keiser Megan
Published: December 2023

Background

Ventilator-associated pneumonia (VAP) is a health care–acquired infection that leads to poor patient outcomes, increased length of hospital stay, exhaustion of health care resources, and unnecessary increases in health care costs.

Objectives

This project was designed to educate registered nurses on the importance of an evidence-based VAP prevention bundle that reduces the overall incidence of VAP infections.

Methods

Patients (N = 146) were enrolled in this quasi-experimental project that took place in a 14-bed neuro trauma surgical burn intensive care unit (ICU) at a level 1 trauma center. Data were collected from the chart review of patients admitted to the neuro trauma surgical burn ICU prior to and after nursing education intervention. The difference in VAP rate and enhanced nursing knowledge were the primary outcome measures.

Results

Data suggest improvement in several patient outcomes. Ventilator days were shortened from 17.45 days to 13.42 days (P = .085), and ICU length of stay decreased from 24.77 days to 17.62 days (P = .035). Patient laboratory data show improved white blood cell values (P < .001), less oxygen requirements (P < .001), and fewer patients meeting the diagnostic criteria for VAP (P = .073).

Discussion

Results suggest there were no statistically significant changes in the knowledge of registered nurses or oral care bundle compliance; however, improvements in patient data following the provider education suggest that continued education to nursing staff will have a positive impact on reducing hospital stay and significant costs associated with a VAP infection.
Novel Method of Dual-innervated Free Gracilis Muscle Transfer for Facial Reanimation: A Case Series
Authors: Hebel Nathan , Boonipat Thanapoom , Robertson Carrie E. , Asaad Malke , Meaike Jesse , Gibreel Waleed , Mardini Samir
Published: December 2023

Background:

Dynamic facial reanimation is the gold standard treatment for a paralyzed face. The use of the cross-face nerve graft (CFNG) in combination with the masseteric nerve to innervate the free gracilis muscle has been reported to provide both spontaneity and strong neural input. We report a case series of dual innervation, using a novel method where the branch to masseter is coapted to the side of the CFNG.

Methods:

Eight patients received free gracilis muscle transfer using the new dual innervation method between September 2014 and December 2017. The CFNG, which was performed nine months prior, was sutured in an end-to-end fashion to the obturator nerve. A nerve graft was coapted to the ipsilateral masseteric nerve and then sutured in an end-to-side fashion to the CFNG proximal to its coaptation to the obturator nerve.

Results:

All patients recovered smile function with and without teeth clenching around the same time period. Smiles without teeth clenching appeared later in two of eight patients and earlier in one of eight patients, being noted at an average of 8.25 months of follow-up versus 7.6 months. The estimate of true attainment is limited by the spacing of follow-up dates. Average follow-up time was 36.07 months (range: 10–71.5). FACE-Gram software smile analysis with and without biting demonstrated similar excursion on average (7.64 mm versus 8.6 mm respectively, P = 0.93), both of which are significantly improved from preoperation.

Conclusion:

This novel method of a dual-innervated free gracilis muscle transfer offers a viable technique that achieves a symmetric, strong, and emotional smile.
ALT Free Flap Coverage after Carotid Endarterectomy in the Setting of Severe Radiation Changes
Authors: Guidry Richard F. , Doran Hannah E. , Stalder Mark W.
Published: December 2023

Carotid endarterectomy with patch angioplasty is commonly performed for severe atherosclerotic disease to reduce stroke risk. After neck radiation, loss of tissue planes; reactive fibrosis of skin; contraction; and rarely, necrosis of skin may occur, leading to severe wound complications and possible exposure of carotid artery reconstruction. Historically, local myocutaneous flaps have been performed to provide soft tissue coverage; however, these procedures may be associated with increased donor site morbidity and can be affected by radiation changes. This report describes the novel use of a fasciocutaneous free flap for durable vascularized soft tissue, and the associated secondary benefit of improved suppleness and range of motion. Additionally, the distant location of the donor site allows for an efficient two-team approach. Here, we describe a patient with severe carotid artery disease with a history of multiple surgical procedures and radiation, which was successfully treated with a carotid endarterectomy and bovine patch angioplasty by vascular surgery and immediate free anterolateral thigh flap coverage by our team.
Complete Reduction of Leg Lymphedema after Liposuction: A 5-Year Prospective Study in 67 Patients without Recurrence
Authors: Karlsson Tobias , Hoffner Mattias , Ohlin Karin , Svensson Barbro , Brorson Håkan
Published: December 2023

Background:

Lymphedema leads to adipose tissue deposition that cannot be removed using conservative methods. Previous studies have shown a complete reduction in excess volume in limbs with lymphedema when treated with liposuction and controlled compression therapy (CCT). We present the long-term outcomes of all patients treated with liposuction and CCT for lower extremity lymphedema (LEL) who were followed up for 5 years.

Methods:

Sixty-seven LEL patients underwent liposuction and CCT. Thirty-six patients had primary lymphedema and 31 patients had secondary lymphedema. The outcomes included excess leg volume over a follow-up period of 5 years. Any association between patient characteristics and treatment outcomes was analyzed.

Results:

The preoperative excess volume prior was 3515 mL [interquartile range (IQR): 2225–5455 mL], and the volume ratio to the unaffected leg was 1.35 (IQR: 1.25–1.53). One year after treatment, the excess volume decreased by 101% (IQR: 84–116). The decrease in excess volume continued during the 5-year follow-up, and at the end of the study, the excess volume had decreased by 115% (IQR: 98–124). No major complications were noted.

Conclusions:

Liposuction and CCT are safe and effective procedures for removing excess adipose tissue and normalizing the leg volume in patients with late-stage LEL. When no satisfactory results are obtained with conservative methods, such as complex decongestive therapy, and there is no or minimal pitting on limb examination, excess adipose tissue is present, and liposuction can be considered.
Sensory Outcomes after Neurotization in Nipple-sparing Mastectomy and Implant-based Breast Reconstruction
Authors: Peled Anne Warren , von Eyben Rie , Peled Ziv M.
Published: December 2023

Background:

Mastectomy and breast reconstruction techniques continue to evolve to optimize aesthetic and reconstructive outcomes. However, the loss of sensation after mastectomy remains a major limitation. This article describes our evolution of a novel approach that we first described in 2019, combining recent advances in breast oncologic, reconstructive, and peripheral nerve surgery to optimize sensory outcomes.

Methods:

Nipple-sparing mastectomy was performed in all patients and involved preservation of lateral intercostal nerves when anatomy was favorable. When nerves could not be preserved without compromising oncologic safety, nipple–areolar complex neurotization was performed using allograft or intercostal autograft from a transected T3, T4, or T5, lateral intercostal nerve to identified subareolar nerve targets. Immediate, prepectoral, direct-to-implant reconstruction was then performed. Acroval one-point moving and one-point static pressure thresholds established baseline sensibility values, which were then repeated at multiple time points postoperatively.

Results:

Outcomes from 47 women (79 breasts) were assessed prospectively. Mean follow-up was 9.2 months (range 6–14 months). At 6 months postoperatively, over 80% of patients had good-to-excellent one-point moving as well as one-point static sensibility scores averaged across all areas tested. None of the patients developed persistent dysesthesia or clinical evidence of neuroma.

Conclusions:

This study represents the largest series reported to date of sensibility outcomes after nipple-sparing mastectomy and implant reconstruction with concurrent neurotization. Sensibility results show that this approach allows for preservation of high degrees of breast and nipple–areolar complex sensation in most patients.
Overexpression of HMGB1 in hepatocytes accelerates PTEN inactivation-induced liver cancer
Authors: Athavale Dipti , Barahona Inés , Song Zhuolun , Desert Romain , Chen Wei , Han Hui , Das Sukanta , Ge Xiaodong , Komakula Sai Santosh B. , Gao Shenglan , Lantvit Daniel , Guzman Grace , Nieto Natalia
Published: December 2023

Background:

Liver cancer is increasing due to the rise in metabolic dysfunction-associated steatohepatitis (MASH). High-mobility group box-1 (HMGB1) is involved in the pathogenesis of chronic liver disease, but its role in MASH-associated liver cancer is unknown. We hypothesized that an increase in hepatocyte-derived HMGB1 in a mouse model of inactivation of PTEN that causes MASH could promote MASH-induced tumorigenesis.

Methods:

We analyzed publicly available transcriptomics datasets, and to explore the effect of overexpressing HMGB1 in cancer progression, we injected 1.5-month-old Pten
∆Hep mice with adeno-associated virus serotype-8 (AAV8) vectors to overexpress HMGB1-EGFP or EGFP, and sacrificed them at 3, 9 and 11 months of age.

Results:

We found that HMGB1 mRNA increases in human MASH and MASH-induced hepatocellular carcinoma (MASH-HCC) compared to healthy livers. Male and female Pten
∆Hep mice overexpressing HMGB1 showed accelerated liver tumor development at 9 and 11 months, respectively, with increased tumor size and volume, compared to control Pten
∆Hep mice. Moreover, Pten
∆Hep mice overexpressing HMGB1, had increased incidence of mixed HCC-intrahepatic cholangiocarcinoma (iCCA). All iCCAs were positive for nuclear YAP and SOX9. Male Pten
∆Hep mice overexpressing HMGB1 showed increased cell proliferation and F4/80+ cells at 3 and 9 months.

Conclusion:

Overexpression of HMGB1 in hepatocytes accelerates liver tumorigenesis in Pten

∆Hep mice, enhancing cell proliferation and F4/80+ cells to drive MASH-induced liver cancer.
Nutrition assessment and MASH severity in children using the Healthy Eating Index
Authors: Jain Ajay Kumar , Buchannan Paula , Yates Katherine P. , Belt Patricia , Schwimmer Jeffrey B. , Rosenthal Philip , Murray Karen F. , Molleston Jean P. , Scheimann Ann , Xanthakos Stavra A. , Behling Cynthia A. , Hertel Paula , Nilson Jamie , Neuschwander-Tetri Brent A. , Tonascia James , Vos Miriam B. ,   for the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
Published: December 2023

Background:

Pediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD.

Methods:

Diet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0–100) and individual food components.

Results:

In all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120 mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43 mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91–1.00), p = 0.04).

Conclusions:

In children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD.
FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways
Authors: Huang Fung-Yu , Wong Danny Ka-Ho , Mak Lung-Yi , Cheung Tan-To , Zhang Sai-Sai , Chau Hau-Tak , Hui Rex Wan-Hin , Seto Wai-Kay , Yuen Man-Fung
Published: December 2023

Background:

Mutation and downregulation of FAT atypical cadherin 4 (FAT4) are frequently detected in HCC, suggesting a tumor suppressor role of FAT4. However, the underlying molecular mechanism remains elusive.

Methods:

CRISPR-Cas9 system was used to knockout FAT4 (FAT4-KO) in a normal human hepatic cell line L02 to investigate the impact of FAT4 loss on the development of HCC. RNA-sequencing and xenograft mouse model were used to study gene expression and tumorigenesis, respectively. The mechanistic basis of FAT4 loss on hepatocarcinogenesis was elucidated using in vitro experiments.

Results:

We found that FAT4-KO disrupted cell-cell adhesion, induced epithelial-mesenchymal transition, and increased expression of extracellular matrix components. FAT4-KO is sufficient for tumor initiation in a xenograft mouse model. RNA-sequencing of FAT4-KO cells identified PAK6-mediated WNT/β-catenin signaling to promote tumor growth. Suppression of PAK6 led to β-catenin shuttling out of the nucleus for ubiquitin-dependent degradation and constrained tumor growth. Further, RNA-sequencing of amassed FAT4-KO cells identified activation of WNT5A and ROR2. The noncanonical WNT5A/ROR2 signaling has no effect on β-catenin and its target genes (CCND1 and c-Myc) expression. Instead, we observed downregulation of receptors for WNT/β-catenin signaling, suggesting the shifting of β-catenin-dependent to β-catenin-independent pathways as tumor progression depends on its receptor expression. Both PAK6 and WNT5A could induce the expression of extracellular matrix glycoprotein, laminin subunit alpha 4. Laminin subunit alpha 4 upregulation in HCC correlated with poor patient survival.

Conclusions:

Our data show that FAT4 loss is sufficient to drive HCC development through the switching of canonical to noncanonical Wingless-type signaling pathways. The findings may provide a mechanistic basis for an in-depth study of the two pathways in the early and late stages of HCC for precise treatment.
Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance
Authors: Teckman Jeffrey , Rosenthal Philip , Ignacio Rosalinda V. , Spino Cathie , Bass Lee M. , Horslen Simon , Wang Kasper , Magee John C. , Karpen Saul , Asai Akihiro , Molleston Jean P. , Squires Robert H. , Kamath Binita M. , Guthery Stephen L. , Loomes Kathleen M. , Shneider Benjamin L. , Sokol Ronald J. ,   for the ChiLDReN (Childhood Liver Disease Research Network)
Published: December 2023

Background:

Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood.

Methods:

The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119).

Results:

We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3–17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not.

Conclusions:

Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.
A review of posterior chamber phakic intraocular lenses
Authors: Reinstein Dan Z. , MacGregor Cheryl , Archer Timothy J. , Gupta Ruchi , Potter Joseph G.
Published: December 2023

Purpose of review

Posterior chamber phakic intraocular lenses (pIOLs) are increasing in popularity as a viable alternative to laser refractive surgery. The purpose of this review is to evaluate the recent updates to pIOLs and to assess the advancements and safety of the procedure.

Recent findings

Accurate lens sizing is the key determinant to suitable vault prediction, advancements to sizing formulae including the use of very high frequency (VHF) digital ultrasound and the application of artificial intelligence and machine learning has led to improved vault prediction and safety. The introduction of the central aquaport has been shown to reduce the formation of cataract and is now adopted in most myopic pIOLs. Recently published studies have demonstrated that pIOLs have an excellent safety profile with no increased risk of retinal detachment or endothelial cell loss. Advancements have led to the introduction of extended depth of focus pIOLs for the correction of presbyopia, further research is required to evaluate the efficacy of new lens designs.

pIOL surgery is experiencing traction with improved lens design and increased lenses choices such as larger optical zone and presbyopic options. Accuracy of implantable collamer lens sizing is paramount to the safety and clinical outcomes, greater predictability is likely to encourage more posterior chamber pIOL users due to fewer sizing related complications.
Uniform Granular Pigmentation as a Novel Dermoscopic Feature of Drug Reaction: A Cross-Sectional Study
Authors: Lu Li-Xia , Zhao Shuang , Chen Ming-Liang , Chen Xiang , Su Juan
Published: December 2023

Objective:

In clinical practice, black-brown-gray pigment granules are common under dermoscopy. However, little is known about their clinical significance. We conducted this study to investigate the relationship between dermoscopy features and their representative pathological features.

Methods:

A cross-sectional study was conducted by searching clinical database in Xiangya Hospital, Central South University, from August 2017 to August 2022. Patients with full information on pigment granules and demographic and pathological findings were entered. Cases were reviewed for information regarding pathological and dermoscopic patterns. Fisher exact test was used to examine the correlation between individual histologic variables and established diagnoses. The depth of pigment granules showed a nonnormal distribution and was analyzed using a nonparametric test.

Results:

In total, data from 83 patients were included in this analysis. The presence of pigment granules under dermoscopy significantly indicated destruction of basal cells or pigment incontinence (91.5%, 76/83). The pigment granules within lesions were divided into uniform and nonuniform patterns with respect to their size, color, and distribution. Uniform granular pigmentation was more likely to be associated with eosinophils (numerous or in aggregates, P < 0.001) or perifollicular inflammatory infiltration in the dermis (P = 0.008). Notably, brown pigment granules (P = 0.024) and uniform granular pigmentation (P < 0.001) were more likely to be induced by medications.

Conclusion:

Uniform granular pigmentation under dermoscopy is a novel indicator of a drug reaction and necessitates a detailed inquiry.
Evaluating Airway Management in Patients With Trisomy 21 in the PICU and Cardiac ICU: A Retrospective Cohort Study
Authors: Wilsterman Eric J. , Nellis Marianne E. , Panisello Josep , Al-Subu Awni , Breuer Ryan , Kimura Dai , Krawiec Conrad , Mallory Palen P. , Nett Sholeen , Owen Erin , Parsons Simon J. , Sanders Ronald C. , Garcia-Marcinkiewicz Annery , Napolitano Natalie , Shults Justine , Nadkarni Vinay M. , Nishisaki Akira ,   for the National Emergency Airway Registry for Children (NEAR4KIDS) and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: December 2023

OBJECTIVES:

Children with trisomy 21 often have anatomic and physiologic features that may complicate tracheal intubation (TI). TI in critically ill children with trisomy 21 is not well described. We hypothesize that in children with trisomy 21, TI is associated with greater odds of adverse airway outcomes (AAOs), including TI-associated events (TIAEs), and peri-intubation hypoxemia (defined as > 20% decrease in pulse oximetry saturation [Spo
2]).

DESIGN:

Retrospective database study using the National Emergency Airway Registry for Children (NEAR4KIDS).

SETTING:

Registry data from 16 North American PICUs and cardiac ICUs (CICUs), from January 2014 to December 2020.

PATIENTS:

A cohort of children under 18 years old who underwent TI in the PICU or CICU from in a NEAR4KIDS center. We identified patients with trisomy 21 and selected matched cohorts within the registry.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We included 8401 TIs in the registry dataset. Children with trisomy 21 accounted for 274 (3.3%) TIs. Among those with trisomy 21, 84% had congenital heart disease and 4% had atlantoaxial instability. Cervical spine protection was used in 6%. The diagnosis of trisomy 21 (vs. without) was associated with lower median weight 7.8 (interquartile range [IQR] 4.5–14.7) kg versus 10.6 (IQR 5.2–25) kg (p < 0.001), and more higher percentage undergoing TI for oxygenation (46% vs. 32%, p < 0.001) and ventilation failure (41% vs. 35%, p = 0.04). Trisomy 21 patients had more difficult airway features (35% vs. 25%, p = 0.001), including upper airway obstruction (14% vs. 8%, p = 0.001). In addition, a greater percentage of trisomy 21 patients received atropine (34% vs. 26%, p = 0.004); and, lower percentage were intubated with video laryngoscopy (30% vs. 37%, p = 0.023). After 1:10 (trisomy 21:controls) propensity-score matching, we failed to identify an association difference in AAO rates (absolute risk difference –0.6% [95% CI –6.1 to 4.9], p = 0.822).

CONCLUSIONS:

Despite differences in airway risks and TI approaches, we have not identified an association between the diagnosis of trisomy 21 and higher AAOs.
Micromonospora parastrephiae sp. nov. and Micromonospora tarensis sp. nov., isolated from the rhizosphere of a Parastrephia quadrangularis plant growing in the Salar de Tara region of the Central Andes in Chile
Authors: Razmilic Valeria , Nouioui Imen , Karlyshev Andrey , Jawad Rana , Trujillo Martha E. , Igual Jose M. , Andrews Barbara A. , Asenjo Juan A. , Carro Lorena , Goodfellow Michael
Published: December 2023

Two novel

Micromonospora

strains, STR1-7T and STR1S-6T, were isolated from the rhizosphere of a Parastrephia quadrangularis plant growing in the Salar de Tara region of the Atacama Desert, Chile. Chemotaxonomic, cultural and phenotypic features confirmed that the isolates belonged to the genus

Micromonospora

. They grew from 20 to 37 °C, from pH7 to 8 and in the presence of up to 3 %, w/v NaCl. The isolates formed distinct branches in

Micromonospora

gene trees based on 16S rRNA gene sequences and on a multi-locus sequence analysis of conserved house-keeping genes. A phylogenomic tree generated from the draft genomes of the isolates and their closest phylogenetic neighbours showed that isolate STR1-7T is most closely related to

Micromonospora orduensis

S2509T, and isolate STR1S-6 T forms a distinct branch that is most closely related to 12 validly named

Micromonospora

species, including

Micromonospora saelicesensis

the earliest proposed member of the group. The isolates were separated from one another and from their closest phylogenomic neighbours using a combination of chemotaxonomic, genomic and phenotypic features, and by low average nucleotide index and digital DNA–DNA hybridization values. Consequently, it is proposed that isolates STR1-7T and STR1S-6T be recognized as representing new species in the genus

Micromonospora

, namely as Micromonospora parastrephiae sp. nov. and Micromonospora tarensis sp. nov.; the type strains are STR1-7T (=CECT 9665T=LMG 30768T) and STR1S-6T (=CECT 9666T=LMG 30770T), respectively. Genome mining showed that the isolates have the capacity to produce novel specialized metabolites, notably antibiotics and compounds that promote plant growth, as well as a broad-range of stress-related genes that provide an insight into how they cope with harsh abiotic conditions that prevail in high-altitude Atacama Desert soils.
Experimental and Computational Analysis of HIFU Thermal Ablation in Breast Cancer Cells: Monolayers vs. Spheroids
Authors: Badawe Heba , Harouz Jean Paul , Abu Kareem , Raad Petra , Ghali Kamel Abou , Kheir Wassim Abou , Khrariche Massoud
Published: December 2023

Objective

The primary objective of our study was to investigate the efficiency of high intensity focused ultrasound (HIFU) ablation in two distinct cellular configurations, 2D monolayers and 3D spheroids of epithelial breast cancer cell lines. The study also compares empirical findings from experiments with results obtained through numerical simulations using a bioheat computational model. This comparison is intended to provide a comprehensive understanding of the acoustic energy conversion within the biological system during HIFU treatment.

Methods

HIFU was applied to 2D and 3D cultured MDA-MB 231 and MCF7 epithelial breast cancer cell lines while systematically varying ultrasound intensity and duty cycle (DC) during sonication sessions of different durations. Temperature elevation was measured and the ablation percentage was calculated based on bright field and fluorescent imaging of the treated regions. Experimental results were validated through simulations of the ablation setup.

Results

Upon HIFU, spheroids exhibited a lower temperature increase (approximately 20 °C) when subjected to comparable acoustic intensities and duty cycles. The level of tumor ablation was highly influenced by DC, with higher DCs leading to greater ablation percentages. However, sonication duration had a minimal impact on the degree of ablation. Numerical simulations corroborated these observations, demonstrating uniform heat distribution within the cultured cells. At higher DCs and intensities, complete ablation of spheroids was achieved, whereas at lower levels, only the outermost layers exhibited ablation.

Conclusion

Our study reveals a significant disparity in the response of 2D monolayers and 3D spheroids to HIFU treatment. Specifically, tumor spheroids require lower temperature elevations for effective ablation, and their ablation percentage significantly increases with elevated DC.
behaviorMate: AnIntranetof Things Approach for Adaptable Control of Behavioral and Navigation-Based Experiments
Authors: Bowler John C. , Zakka George , Yong Hyun Choong , Li Wenke , Rao Bovey , Liao Zhenrui , Priestley James B. , Losonczy Attila
Published: December 2023

1

Investigators conducting behavioral experiments often need precise control over the timing of the delivery of stimuli to subjects and to collect the precise times of the subsequent behavioral responses. Furthermore, investigators want fine-tuned control over how various multi-modal cues are presented. behaviorMate takes an “Intranet of Things” approach, using a networked system of hardware and software components for achieving these goals. The system outputs a file with integrated timestamp-event pairs that investigators can then format and process using their own analysis pipelines. We present an overview of the electronic components and GUI application that make up behaviorMate as well as mechanical designs for compatible experimental rigs to provide the reader with the ability to set up their own system. A wide variety of paradigms are supported, including goal-oriented learning, random foraging, and context switching. We demonstrate behaviorMate’s utility and reliability with a range of use cases from several published studies and benchmark tests. Finally, we present experimental validation demonstrating different modalities of hippocampal place field studies. Both treadmill with burlap belt and virtual reality with running wheel paradigms were performed to confirm the efficacy and flexibility of the approach. Previous solutions rely on proprietary systems that may have large upfront costs or present frameworks that require customized software to be developed. behaviorMate uses open-source software and a flexible configuration system to mitigate both concerns. behaviorMate has a proven record for head-fixed imaging experiments and could be easily adopted for task control in a variety of experimental situations.
Deep representation learning of electrocardiogram reveals novel insights in cardiac structure and functions and connections to cardiovascular diseases
Authors: Yeung Ming Wai , van de Leur Rutger R , Benjamins Jan Walter , Vessies Melle B. , Ruijsink Bram , Puyol-Antón Esther , van Tintelen J. Peter , Verweij Niek , van Es Rene , van der Harst Pim
Published: December 2023

Background

Conventional approaches to analysing electrocardiograms (ECG) in fragmented parameters (such as the PR interval) ignored the high dimensionality of data which might result in omission of subtle information content relevant the cardiac biology. Deep representation learning of ECG may reveal novel insights.

Methods

We finetuned an unsupervised variational auto-encoder (VAE), originally trained on over 1.1 million 12-lead ECG, to learn the underlying distributions of the median beat ECG morphology of 41,927 UK Biobank participants. We explored the relationship between the latent representations (latent factors) and traditional ECG parameters, cardiac magnetic resonance (CMR)-derived structural and functional phenotypes. We assessed the association of the latent factors with various cardiac and cardiometabolic diseases and further investigated their predictive value for cardiovascular mortality. Finally, we studied genetic components of the latent factors by genome wide association study (GWAS).

Results

The latent factors showed differential correlation patterns with conventional ECG parameters with the highest correlations observed in factor 8 and PR interval (r=0.76). Multivariable analyses of the ECG latent factors recapitulated CMR-derived parameters with a better performance for the left ventricle than the right. We saw higher performance in models for structural parameters than functional parameters and observed the highest adjusted R2of 0.488 for left ventricular LV end-diastolic mass (LVEDM). The latent factors showed strong association with cardiac diseases. This included bundle branch block and latent factor 28 (OR= 2.72 [95% confidence interval CI,2.46-3.01] per standard deviation, SD change); per SD change of latent factor 27 was associated with cardiomyopathy (OR=2.38, 95%CI 1.97-2.89) and heart failure (OR=1.94, 95%CI 1.71-2.21). In the GWAS of the latent factors, we identified 170 genetic loci with 29 not previously associated with electrocardiographic traits. Following up with bioinformatic analyses, we found the genetic signals involved in cardiac development, contractility and electrophysiology.

Conclusions

Deep representation learning of 12-lead ECG provided not only clinically meaningful but also novel insights into cardiac biology and cardiovascular health.

Graphical abstract