bluuebunny/crossref_metadata_2025 huggingface dataset:
A review on the colours, flavours and shapes used in paediatric 3D printed oral solid dosage forms
Authors: Vlachou Marilena , Siamidi Angeliki , Protopapa Chrystalla , Sotiropoulou Ioanna
Published: March 2023

Objectives

This review aims at gleaning the currently available research reports that relate to 3D printlets for paediatric patients and especially the excipients used to produce various colours, flavours, shapes and sizes.

Methods

A thorough literature review on paediatric 3D printed oral solid dosage forms, focusing on the use of colours, flavours and various shapes/dimensions, was conducted with an adjusted time frame between 2017 and 2022.

Key findings

3D printlets for the paediatric population include the chewable dosage forms (including solid forms and soft forms or gummies), the swallowing dosage forms and the orodispersable dosage forms (printlets or films). Researchers have tested many colours, flavours, shapes and dimensions for chewable formulation production using pectin and gelatin to create gummies or chocolate and cereals. Scientists have also used many methods and excipients to produce printlets with various colours, flavours, shapes and small sizes (minitablets or minicaplets) for the swallowing dosage forms. Concerning the orodispersable’s, the research was rather limited.

Conclusions

Compared with conventional oral dosage form manufacturing processes, 3D printing techniques use a different approach. More specifically, these techniques can provide personalisation of dose, shape, size, taste, colour and appropriate drug release rates, which is of paramount importance, especially for paediatric patients. With the correct excipients, the printlets can serve as ideal dosage forms candidates for the treatment of the paediatric population.
Providing Digital Technology Training as a Way to Retain Older Workers: The Importance of Perceived Usefulness and Growth Need
Authors: Xie Hanji , Fang Yanran , Wang Mo , Liu Junming , Lv Aiqin
Published: March 2023

The increasing prevalence of aging workforce around the globe renders older worker retention an integral approach for organizations to maintain human capital. In the meantime, the increasing application of digital technologies at work poses new challenges for older workers. Providing digital technology training is therefore considered as a potential approach to retaining older workers. Yet, we have limited knowledge about the role played by digital technology training availability in facilitating older worker retention. Addressing this important research void, we examine the motivation-based (i.e., autonomy need satisfaction at work) and the ability-based (i.e., competence need satisfaction at work) mechanisms that transmit the positive indirect effects of digital technology training availability on older workers’ intention to remain. We also examine the critical roles of the relevance of the training (both the relevance to the situation and to the participant) in shaping the impacts of digital technology training availability. Analyzing data collected from 285 workers aged 40 years or older, we found that when digital technology was perceived to be more (vs. less) useful at work, digital technology training availability indirectly facilitated older workers’ intention to remain via both autonomy and competence needs satisfaction at work. Moreover, the amplifying effects of perceived usefulness of digital technology at work were more (vs. less) pronounced for participants who had higher (vs. lower) growth need. Theoretical and practical implications were also discussed based on our findings.
Disparities in Unilateral Do Not Resuscitate Order Use During the COVID-19 Pandemic*
Authors: Piscitello Gina M. , Tyker Albina , Schenker Yael , Arnold Robert M. , Siegler Mark , Parker William F.
Published: March 2023

OBJECTIVES:

A unilateral do-not-resuscitate (UDNR) order is a do-not-resuscitate order placed using clinician judgment which does not require consent from a patient or surrogate. This study assessed how UDNR orders were used during the COVID-19 pandemic.

DESIGN:

We analyzed a retrospective cross-sectional study of UDNR use at two academic medical centers between April 2020 and April 2021.

SETTING:

Two academic medical centers in the Chicago metropolitan area.

PATIENTS:

Patients admitted to an ICU between April 2020 and April 2021 who received vasopressor or inotropic medications to select for patients with high severity of illness.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The 1,473 patients meeting inclusion criteria were 53% male, median age 64 (interquartile range, 54–73), and 38% died during admission or were discharged to hospice. Clinicians placed do not resuscitate orders for 41% of patients (n = 604/1,473) and UDNR orders for 3% of patients (n = 51/1,473). The absolute rate of UDNR orders was higher for patients who were primary Spanish speaking (10% Spanish vs 3% English; p ≤ 0.0001), were Hispanic or Latinx (7% Hispanic/Latinx vs 3% Black vs 2% White; p = 0.003), positive for COVID-19 (9% vs 3%; p ≤ 0.0001), or were intubated (5% vs 1%; p = 0.001). In the base multivariable logistic regression model including age, race/ethnicity, primary language spoken, and hospital location, Black race (adjusted odds ratio [aOR], 2.5; 95% CI, 1.3–4.9) and primary Spanish language (aOR, 4.4; 95% CI, 2.1–9.4) had higher odds of UDNR. After adjusting the base model for severity of illness, primary Spanish language remained associated with higher odds of UDNR order (aOR, 2.8; 95% CI, 1.7–4.7).

CONCLUSIONS:

In this multihospital study, UDNR orders were used more often for primary Spanish-speaking patients during the COVID-19 pandemic, which may be related to communication barriers Spanish-speaking patients and families experience. Further study is needed to assess UDNR use across hospitals and enact interventions to improve potential disparities.
Electron Transport Chain Inhibition to Decrease Injury in Transplanted Donation After Circulatory Death Rat Hearts
Authors: Quader Mohammed , Chen Qun , Akande Oluwatoyin , Cholyway Renee , Mezzaroma Eleonora , Lesnefsky Edward J. , Toldo Stefano
Published: March 2023

Donation after circulatory death (DCD) donor hearts sustain ischemic damage and are not routinely used for heart transplantation. DCD heart injury, particularly reperfusion injury, is primarily mediated by releasing reactive oxygen species from the damaged mitochondria (complex I of the electron transport chain). Amobarbital (AMO) is a transient inhibitor of complex I and is known to reduce releasing reactive oxygen species generation. We studied the beneficial effects of AMO in transplanted DCD hearts. Sprague-Dawley rats were assigned to 4 groups—DCD or DCD + AMO donors and control beating-heart donors (CBD) or CBD + AMO donors (n = 6–8 each). Anesthetized rats were connected to a ventilator. The right carotid artery was cannulated, heparin and vecuronium were administered. The DCD process started by disconnecting the ventilator. DCD hearts were procured after 25 minutes of in-vivoischemia, whereas CBD hearts were procured without ischemia. At procurement, all donor hearts received 10 mL of University of Wisconsin cardioplegia solution. The CBD + AMO and DCD + AMO groups received AMO (2 mM) dissolved in cardioplegia. Heterotopic heart transplantation was performed by anastomosing the donor aorta and pulmonary artery to the recipient's abdominal aorta and inferior vena cava. After 14 days, transplanted heart function was measured with a balloon tip catheter placed in the left ventricle. Compared with CBD hearts, DCD hearts had significantly lower developed pressure. AMO treatment significantly improved cardiac function in DCD hearts. Treatment of DCD hearts at the time of reperfusion with AMO resulted in an improvement of transplanted heart function that was comparable with the CBD hearts.
The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action
Authors: Fioredda Francesca , Skokowa Julia , Tamary Hannah , Spanoudakis Michail , Farruggia Piero , Almeida Antonio , Guardo Daniela , Höglund Petter , Newburger Peter E. , Palmblad Jan , Touw Ivo P. , Zeidler Cornelia , Warren Alan J. , Dale David C. , Welte Karl , Dufour Carlo , Papadaki Helen A.
Published: March 2023

Neutropenia, as an isolated blood cell deficiency, is a feature of a wide spectrum of acquired or congenital, benign or premalignant disorders with a predisposition to develop myelodysplastic neoplasms/acute myeloid leukemia that may arise at any age. In recent years, advances in diagnostic methodologies, particularly in the field of genomics, have revealed novel genes and mechanisms responsible for etiology and disease evolution and opened new perspectives for tailored treatment. Despite the research and diagnostic advances in the field, real world evidence, arising from international neutropenia patient registries and scientific networks, has shown that the diagnosis and management of neutropenic patients is mostly based on the physicians’ experience and local practices. Therefore, experts participating in the European Network for the Innovative Diagnosis and Treatment of Chronic Neutropenias have collaborated under the auspices of the European Hematology Association to produce recommendations for the diagnosis and management of patients across the whole spectrum of chronic neutropenias. In the present article, we describe evidence- and consensus-based guidelines for the definition and classification, diagnosis, and follow-up of patients with chronic neutropenias including special entities such as pregnancy and the neonatal period. We particularly emphasize the importance of combining the clinical findings with classical and novel laboratory testing, and advanced germline and/or somatic mutational analyses, for the characterization, risk stratification, and monitoring of the entire spectrum of neutropenia patients. We believe that the wide clinical use of these practical recommendations will be particularly beneficial for patients, families, and treating physicians.
Complement Inhibition for Geographic Atrophy: Review of Salient Functional Outcomes and Perspective
Authors: Spaide Richard F. , Vavvas Demetrios G.
Published: March 2023

Purpose:

To evaluate available rationale and outcomes of randomized trial results for complement inhibition for geographic atrophy.

Methods:

Data from recently completed randomized trials of complement inhibition, particularly for pegcetacoplan and avacincaptad pegol, were evaluated for both the outcome, area of autofluorescence loss, and functional vision tests.

Results:

Pegcetacoplan 2 mg showed statistically significant reduction in expansion of area of autofluorescence loss with monthly, but not every-other-month dosing, in a 12-month phase 2 trial. Nearly 40% of patients recruited for the monthly arm did not complete the trial. In two parallel phase 3 studies there was a statistically significant reduction in the area of atrophy in one but not both studies. Data released at 24 months follow-up showed statistically significant reduction in area of autofluorescence detected atrophy in both studies compared with sham. Patients did not show functional difference in best corrected visual acuity, maximum reading speed, Functional Reading Independence Index, and mean microperimetry threshold sensitivities in the treatment versus sham arms. Avacincaptad pegol was evaluated in 2 randomized pivotal studies and showed a statistically significant reduction in expansion of autofluorescence loss at 12 months. Patients in the treatment arms did not show any difference as compared with sham in best corrected visual acuity or low luminance visual acuity, the only functional outcomes mentioned. Both drugs increased the risk of macular neovascularization.

Conclusions:

Both avacincaptad pegol and pegcetacoplan show significant differences compared with sham in autofluorescence imaging but no benefit in visual function at 12 and 24 months, respectively.
EXTENSIVE SUBRETINAL FIBROSIS ASSOCIATED WITH PSEUDOXANTHOMA ELASTICUM
Authors: Oyeniran Enny , Wiley Henry , Bellur Sunil , Sen H. Nida , Ferreira Carlos R. , Chew Emily Y. , Kodati Shilpa
Published: March 2023

Purpose:

The purpose of this study was to report an unusual case of pseudoxanthoma elasticum presenting with an inflammatory phenotype associated with atypical and rapidly progressive subretinal fibrosis.

Methods:

This was an observational case report.

Results:

A patient with a history of pseudoxanthoma elasticum presented with rapidly progressive subretinal fibrosis, particularly in the left eye, over the course of one year. The patient was noted at presentation to have intraocular inflammation, outer retinal attenuation, multifocal choroiditis–like lesions, and intraretinal fluid (in the absence of obvious clinical or angiographic signs of exudative choroidal neovascular membranes). An ocular inflammatory phenotype was diagnosed, and the patient was treated with a combination of local steroids and systemic corticosteroids/immunomodulatory agents. After initiation of these agents, the patient demonstrated functional and structural improvement, with partial outer retinal reconstitution, decreased intraretinal fluid, and lack of further progression of subretinal fibrosis.

Conclusion:

This report describes an inflammatory phenotype of pseudoxanthoma elasticum associated with severe and atypical subretinal fibrosis. This case expands upon the currently known spectrum of inflammatory phenotypes associated with pseudoxanthoma elasticum. Treatment with corticosteroids or immunomodulatory treatment should be considered in similar cases.
Desperate Times Call for Desperate Measures: Bridging to Transplant in the Face of Central Device Infection
Authors: Jenkins Haley , Starling Randall C. , Soltesz Edward G. , Tong Michael Z.Y. , Weiss Aaron J.
Published: March 2023

Patients with durable left ventricular assist devices (LVAD) that develop central device infections can prove prohibitively challenging to treat and may require device explant for source control. In bridge to transplant (BTT) LVAD patients, the management of mediastinal infection is further complicated by changes in the 2018 United Network of Organ Sharing (UNOS) allocation system, which resulted in a comparatively lower listing status than in its previous iteration.

We present the case of a 36-year-old male with nonischemic cardiomyopathy status post Heartmate 3 (HM3) implantation as BTT who after a year of stable HM3 support, developed a severe bacterial infection along the outflow graft. Despite attempts at finding a suitable donor at his current listing, his clinical status continued to deteriorate. To obtain infection source control, he underwent LVAD explant and insertion of a left axillary artery Impella 5.5 ventricular assist device for necessary hemodynamic support. The patient’s listing was upgraded to Status 2, and following the identification of a suitable donor, underwent successful heart transplantation. This case highlights the limitation of the updated UNOS heart allocation system for patients with central device infections and describes the successful use of salvage temporary mechanical circulatory support to bridge to transplantation.
Secondary breast reconstruction in small to medium-sized irradiated breasts: could Fat-Augmented LD (FALD) flap be a reliable alternative?
Authors: Longo Benedetto , D’Orsi Gennaro , Vanni Gianluca , Gagliano Elettra , Buonomo Claudio Oreste , Cervelli Valerio
Published: March 2023

Background:

Secondary breast reconstruction (BR) is recognized as challenging procedure particularly when radiotherapy (RT) has previously been performed. The aim of the study was to compare operative data and aesthetic outcomes between secondary irradiated and immediate BR using Fat-Augmented Latissimus Dorsi (FALD) flap.

Methods:

We conducted a prospective clinical study between September 2020 and September 2021. Patients were divided into 2 groups: Group A included secondary BR using FALD flap in previously irradiated breasts, while Group B immediate BR with FALD flap. Demographics and surgical data were compared and an aesthetic analysis was performed. Chi-square and t-test were performed for categorical and continuous variables respectively.

Results:

20 FALD flap-based BR for each group were included. The two groups were found to be homogeneous for the demographic’s variables. The difference in mean operative time (263.1 vs 265.1 min; p=0.467) and complications (p=0.633) among the two groups were not significant. There was statistically significant difference in term of immediate fat grafting volume in favor of group A (218.2 cc vs 133.0 cc; p<0.0001). Regarding aesthetic outcomes, the mean global score evaluation showed no statistically significant differences between groups (17.86 vs 18.21; p=0.209).

Conclusion:

Our study states that the FALD flap can be considered a reliable procedure for secondary reconstruction in previously irradiated breasts, although it is not indicated for patients with larger breasts. This surgical technique allowed us to achieve a totally autologous BR with good aesthetic results and low complication rates, even in secondary irradiated cases.

Level of Evidence III
Late Presenting Sagittal Craniosynostosis: An Update to a Standardized Treatment Protocol
Authors: Beiriger Justin W. , Bruce Madeleine K. , Mak Allison , Zhang Casey , Kueper Janina , Irgebay Zhazira , Smetona John , Pfaff Miles , Bykowski Michael , Losee Joseph E. , Goldstein Jesse A.
Published: March 2023

Background:

We previously published our protocol to treat patients who present with sagittal craniosynostosis after the age of one year. The purpose of this study is to present a follow-up and update of this cohort to evaluate outcomes of our treatment protocol.

Methods

Patients with isolated sagittal craniosynostosis who presented after the age of one year between July 2013 and April 2021 were included.

Results

108 patients met inclusion criteria. The average age at presentation was 5.2 ± 3.4 years and 79 (73.1%) were male. The indications for imaging were head shape (54.6%), headache (14.8%), trauma (9.3%), seizure (4.6%), papilledema (2.8%), and other (13.9%). Of the 108 patients, 12 (11.1%) underwent surgery following their initial consultation: 5 for papilledema, 4 for elevated ICP, 2 for severely scaphocephalic head shapes, and 1 for abnormal fundoscopic findings. Two of these patients underwent additional reconstructive surgery, one for the recurrence of papilledema and headache and the other for progressive scaphocephaly. The average length of time between surgeries was 4.9 years. Of the 96 patients who were conservatively managed, 4 (4.2%) underwent surgery at an average of 1.2 ± 0.5 years later (average age 4.4 ± 1.5 years) for brain growth restriction (n=2), aesthetic concerns (n=1), and refractory headaches (n=1). The average follow-up of all patients with craniofacial surgery was 2.7 ± 2.3 years (median 2.1 years, IQR 3.7 years).

Conclusions

Patients with late-presenting sagittal craniosynostosis require surgical correction less often than younger patients, likely due to milder phenotype. Few patients in the conservative treatment arm ultimately required surgery (4%).
Editorial: A Tribute to Mediterranean Pioneers in Facial Plastic and Craniomaxillofacial Surgery
Authors: Hallak Hana , Sharaf Basel A.
Published: March 2023

Background:

Physicians from the Mediterranean civilization were profoundly instrumental in the early development and contemporary advancement of the craniomaxillofacial field. These feats are scarcely studied or acclaimed. In this editorial, the authors explore the contributions of these major Mediterranean pioneers.

Methods:

A literature review on the subject was performed using PubMed, Scopus, Embase, and Mayo Clinic Libraries.

Results:

Mediterranean medicine has recognized and managed craniomaxillofacial pathologies from as early as the 10th century. The first inscriptions were authored by Abu Alkasem al-Zahrawi and Serefeddin Sabuncuoglu. Starting in the 15th century, Leonardo da Vinci shed light on anatomy and esthetics at a time where Gasparo Tagliacozzi spearheaded maxillofacial techniques. The field during the Renaissance was dominated by Hippocrates Asclepiades. Varaztad Kazanjian revolutionized the armamentarium necessitated by mass emergencies during the World War. In the 20th century, Paul Tessier redefined the limits of craniomaxillofacial treatment by using facial osteotomies and developing refined surgical instruments. Modern day Sam Hamra, Enrico Robotti, and Daniel Labbé continue to lead educational and innovative fronts of the field.

Conclusions:

This essay highlights some important historical contributions to the fields of craniomaxillofacial and facial plastic surgery by pioneer surgeons from around the Mediterranean.
Efficacy of Strategies Intended to Prevent Surgical Site Infection After Lower Limb Revascularization Surgery
Authors: Kirkham Aidan M. , Candeliere Jasmine , McIsaac Daniel I. , Stelfox Henry T. , Dubois Luc , Gill Heather L. , Brandys Timothy , Nagpal Sudhir K. , Roberts Derek J.
Published: March 2023

Objective:

The objective of this study is to evaluate the efficacy of strategies intended to prevent surgical site infection (SSI) after lower limb revascularization surgery.

Background:

SSIs are common, costly complications of lower limb revascularization surgery associated with significant morbidity and mortality.

Methods:

We searched MEDLINE, EMBASE, CENTRAL, and Evidence-Based Medicine Reviews (inception to April 28, 2022). Two investigators independently screened abstracts and full-text articles, extracted data, and assessed the risk of bias. We included randomized controlled trials (RCTs) that evaluated strategies intended to prevent SSI after lower limb revascularization surgery for peripheral artery disease. We used random-effects models to pool data and GRADE to assess certainty.

Results:

Among 6258 identified citations, we included 26 RCTs (n=4752 patients) that evaluated 12 strategies to prevent SSI. Preincision antibiotics [risk ratio (RR)=0.25; 95% CI, 0.11–0.57; n=4 studies; I
2 statistic=7.1%; high certainty] and incisional negative-pressure wound therapy (iNPWT) (RR=0.54; 95% CI, 0.38–0.78; n=5 studies; I
2 statistic=7.2%; high certainty) reduced pooled risk of early (≤30 days) SSI. iNPWT also reduced the risk of longer-term (>30 days) SSI (pooled-RR=0.44; 95% CI, 0.26–0.73; n=2 studies; I
2=0%; low certainty). Strategies with uncertain effects on risk of SSI included preincision ultrasound vein mapping (RR=0.58; 95% CI, 0.33–1.01; n=1 study); transverse groin incisions (RR=0.33; 95% CI, 0.097–1.15; n=1 study), antibiotic-bonded prosthetic bypass grafts (RR=0.74; 95% CI, 0.44–1.25; n=1 study; n=257 patients), and postoperative oxygen administration (RR=0.66; 95% CI, 0.42–1.03; n=1 study) (low certainty for all).

Conclusions:

Preincision antibiotics and iNPWT reduce the risk of early SSI after lower limb revascularization surgery. Confirmatory trials are required to determine whether other promising strategies also reduce SSI risk.
Variation of Liver Transplant Practice and Outcomes During Public Holidays in the United States: Analysis of United Network for Organ Sharing Registry
Authors: Shamaa Tayseer M. , Kitajima Toshihiro , Ivanics Tommy , Shimada Shingo , Mohamed Adhnan , Yeddula Sirisha , Rizzari Michael , Collins Kelly , Yoshida Atsushi , Abouljoud Marwan , Nagai Shunji
Published: March 2023

Background:

It has been reported that patients hospitalized outside regular working hours have worse outcomes. This study aims to compare outcomes following liver transplantation (LT) performed during public holidays and nonholidays.

Methods:

We analyzed the United Network for Organ Sharing registry data for 55 200 adult patients who underwent an LT between 2010 and 2019. Patients were grouped according to LT receipt during public holidays ±3 d (n = 7350) and nonholiday periods (n = 47 850). The overall post-LT mortality hazard was analyzed using multivariable Cox regression models.

Results:

LT recipient characteristics were similar between public holidays and nonholidays. Compared with nonholidays, deceased donors during public holidays had a lower donor risk index (median [interquartile range]: holidays 1.52 [1.29–1.83] versus nonholidays 1.54 [1.31–1.85]; P = 0.001) and shorter cold ischemia time (median [interquartile range]: holidays 5.82 h [4.52–7.22] versus nonholidays 5.91 h [4.62–7.38]; P < 0.001). Propensity score matching 4-to-1 was done to adjust for donor and recipient confounders (n = 33 505); LT receipt during public holidays (n = 6701) was associated with a lower risk of overall mortality (hazard ratio 0.94 [95% confidence interval, 0.86-0.99]; P = 0.046). The number of livers that were not recovered for transplant was higher during public holidays compared with nonholidays (15.4% versus 14.5%, respectively; P = 0.03).

Conclusions:

Although LT performed during public holidays was associated with improved overall patient survival, liver discard rates were higher during public holidays compared with nonholidays.
Admixture Mapping of Peripheral Artery Disease in a Dominican Population Reveals a Novel Risk Locus on 2q35
Authors: Cullina Sinead , Wojcik Genevieve L. , Shemirani Ruhollah , Klarin Derek , Gorman Bryan R. , Sorokin Elena P. , Gignoux Christopher R. , Belbin Gillian M. , Pyarajan Saiju , Asgari Samira , Tsao Phil S. , Damrauer Scott M. , Abul-Husn Noura S. , Kenny Eimear E.
Published: March 2023

Peripheral artery disease (PAD) is a form of atherosclerotic cardiovascular disease, affecting ∼8 million Americans, and is known to have racial and ethnic disparities. PAD has been reported to have significantly higher prevalence in African Americans (AAs) compared to non-Hispanic European Americans (EAs). Hispanic/Latinos (HLs) have been reported to have lower or similar rates of PAD compared to EAs, despite having a paradoxically high burden of PAD risk factors, however recent work suggests prevalence may differ between sub-groups. Here we examined a large cohort of diverse adults in the BioMebiobank in New York City (NYC). We observed the prevalence of PAD at 1.7% in EAs vs 8.5% and 9.4% in AAs and HLs, respectively; and among HL sub-groups, at 11.4% and 11.5% in Puerto Rican and Dominican populations, respectively. Follow-up analysis that adjusted for common risk factors demonstrated that Dominicans had the highest increased risk for PAD relative to EAs (OR=3.15 (95% CI 2.33-4.25),P<6.44×10-14). To investigate whether genetic factors may explain this increased risk, we performed admixture mapping by testing the association between local ancestry (LA) and PAD in Dominican BioMeparticipants (N=1,940) separately for European (EUR), African (AFR) and Native American (NAT) continental ancestry tracts. We identified a NAT ancestry tract at chromosome 2q35 that was significantly associated with PAD (OR=2.05 (95% CI 1.51-2.78),P<4.06×10-6) with 22.5% vs 12.5% PAD prevalence in heterozygous NAT tract carriers versus non-carriers, respectively. Fine-mapping at this locus implicated tag SNP rs78529201 located within a long intergenic non-coding RNA (lincRNA)LINC00607, a gene expression regulator of key genes related to thrombosis and extracellular remodeling of endothelial cells, suggesting a putative link of the 2q35 locus to PAD etiology. In summary, we showed how leveraging health systems data helped understand nuances of PAD risk across HL sub-groups and admixture mapping approaches elucidated a novel risk locus in a Dominican population.
Click-to-Release: Cleavable Radioimmunoimaging with89Zr-DFO-Trans-Cyclooctene-Trastuzumab Increases Tumor-to-Blood Ratio
Authors: Vlastara Maria , Rossin Raffaella , Hoeben Freek J.M. , de Roode Kim E. , Boswinkel Milou , Kleijn Laurens H.J. , Nagarajah James , Rijpkema Mark , Robillard Marc S.
Published: March 2023

One of the main challenges of PET imaging with89Zr-labeled monoclonal antibodies (mAbs) remains the long blood circulation of the radiolabeled mAbs, leading to high background signals, decreasing image quality. To overcome this limitation, here we report the use of a bioorthogonal linker cleavage approach (click-to-release chemistry) to selectively liberate [89Zr]Zr-DFO fromtrans-cyclooctene-functionalized trastuzumab (TCO-Tmab) in blood, following the administration of a tetrazine compound (trigger) in BT-474 tumor-bearing mice.

Methods

We created a series of TCO-DFO constructs and evaluated their performance in [89Zr]Zr-DFO release from Tmab in vitro using different trigger compounds. The in vivo behavior of the best performing [89Zr]Zr-TCO-Tmab was studied in healthy mice first, to determine the optimal dose of the trigger. To find the optimal time for the trigger administration, the rate of [89Zr]Zr-TCO-Tmab internalization was studied in BT-474 cancer cells. Finally, the trigger was administered 6 h or 24 h after [89Zr]Zr-TCO-Tmab-administration in tumor-bearing mice to liberate the [89Zr]Zr-DFO fragment. PET scans were obtained of tumor-bearing mice that received the trigger 6 h post-[89Zr]Zr-TCO-Tmab administration.

Results

The [89Zr]Zr-TCO-Tmab and trigger pair with the best in vivo properties exhibited 83% release in 50 % mouse plasma. In tumor-bearing mice the tumor-blood ratios were markedly increased from 1.0 ± 0.4 to 2.3 ± 0.6 (p=0.0057) and from 2.5 ± 0.7 to 6.6 ± 0.9 (p<0.0001) when the trigger was administered at 6 h and 24 h post-mAb, respectively. Same day PET imaging clearly showed uptake in the tumor combined with a strongly reduced background due to the fast clearance of the released [89Zr]Zr-DFO-containing fragment from the circulation through the kidneys.

Conclusions

This is the first demonstration of the use oftrans-cyclooctene-tetrazine click-to-release chemistry to release a radioactive chelator from a mAb in mice to increase tumor-blood ratios. Our results suggest that click-cleavable radioimmunoimaging may allow for substantially shorter intervals in PET imaging with full mAbs, reducing radiation doses and potentially even enabling same day imaging.
Mutation nsp6 L232F associated with MERS-CoV zoonotic transmission confers higher viral replication in human respiratory tract cultures ex-vivo
Authors: So Ray TY , Chu Daniel KW , Hui Kenrie PY , Mok Chris KP , Sanyal Sumana , Nicholls John M , Ho John C. W. , Cheung Man-chun , Ng Ka-chun , Yeung Hin-Wo , Chan Michael CW , Poon Leo LM , Zhao Jincun , Peiris Malik
Published: March 2023

Middle East respiratory syndrome coronavirus (MERS-CoV) causes zoonotic disease. Dromedary camels are the source of zoonotic infection. We identified a mutation of amino acid leucine to phenylalanine in the codon 232 position of the non-structural protein 6 (nsp6) (nsp6 L232F) that is repeatedly associated with zoonotic transmission. We generated a pair of isogenic recombinant MERS-CoV with nsp6 232L and 232F residues, respectively, and showed that the nsp6 L232F mutation confers higher replication competence in ex-vivo culture of human nasal and bronchial tissues and in lungs of mice experimentally infected in-vivo. Mechanistically, the nsp6 L232F mutation appeared to modulate autophagy and was associated with higher exocytic virus egress, while innate immune responses and zippering activity of the endoplasmic reticulum remained unaffected. Our study suggests that MERS-CoV nsp6 may contribute to viral adaptation to humans. This highlights the importance of continued surveillance of MERS-CoV in both camels and humans.

Importance

Viral host adaptation plays an important role in zoonotic transmission of coronaviruses. For MERS-CoV that widely circulates in dromedary camels from Arabian Peninsula, camel-to human transmissions are ongoing, raising the possibility of human adaptive evolution for MERS-CoV. Here, we analysed MERS-CoV sequences and identified an amino acid mutation L232F in nsp6 to occur repeatedly in human MERS-CoV over the years since the first outbreak in 2012. We found the nsp6 L232F confers increase viral replication in-vitro, in ex-vivo upper human respiratory tract cultures and in mice, using a reverse genetics approach. Our results showed the nsp6 L232F may be advantageous for MERS-CoV to replicate in humans. This study highlighted a human adaptation of MERS-CoV and a need for continued surveillance of MERS-CoV to identify any further adaptations in humans, which may be relevant to the pandemic potential of MERS-CoV.
IDoser: Improving individualized dosing policies with clinical practice and machine learning
Authors: Correa Nuria , Cerquides Jesus , Vassena Rita , Popovic Mina , Arcos Josep Lluis
Published: March 2023

Background

Finding the correct drug dose for a specific condition is a key step in many treatments, and failing to do so can lead to deleterious consequences to patient health. Clinical protocols are derived from drug development phase prospective trials. While carefully designed, these often do not include all potential patients, comorbidities or clinical outcomes, ultimately leading to sub-optimal dosing policies. Observational datasets provide real-world information that cannot be substituted with data collected in a controlled environment. Several published methodologies have applied observational datasets for the development of clinical protocols, however these are only applicable whenever these datasets are varied and complete. Often, clinical observational datasets do not comply with these requirements. Computational methods can and should exploit field knowledge to address weaknesses associated with clinical observational data.

Methods

This paper proposes IDoser, a core dosing model that links drug dose to relevant covariates via a set of coefficients, and includes a loss function to codify needed assumptions and requirements. Coordinate descent is used to obtain a fitted model with minimal loss. The loss function is also used to measure performance when validating the model with unseen data. Our proposal is validated using the case of follicle stimulating hormone (FSH) dosing for controlled ovarian stimulation (COS).

Results

The proposed Individualized Doser (IDoser) achieved significant improvements when loss values were compared to observed clinical practice and a selected literature benchmark and during the validation phase.

Conclusions

This methodology constitutes a simple but effective method to bridge the gap between current clinical dosing policies and gold policies based on the true underlying and often unknown dose-response functions.
Association of 24-hour activity patterns with risk of Alzheimer’s disease, Parkinson’s disease, and cognitive decline
Authors: Winer Joseph R. , Lok Renske , Weed Lara , He Zihuai , Poston Kathleen L. , Mormino Elizabeth C. , Zeitzer Jamie M.
Published: March 2023

Sleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer’s disease (AD) and Parkinson’s disease (PD). Assessment of 24-hour rhythm impairment may serve as an early indicator of disease and cognitive decline. Our objective was to determine whether objective markers of 24-hour activity are associated with subsequent development of AD, PD, and cognitive decline. This longitudinal study obtained UK Biobank data from 82,829 individuals with valid accelerometer data (collected from June 2013 to January 2016) out of 103,671 eligible adults aged 40 to 79 years with a mean (±SD) follow-up of 6.8 (±0.9) years. AD and PD diagnoses were ascertained through September 2021, with data analysis conducted March to November 2022. The outcomes were accelerometer-derived measures of 24-hour activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), longitudinal tests of cognitive function, and demographic characteristics. 82,829 participants consisted of 46,683 women (56%) and 36,146 men (44%) with a mean (±SD) age of 62.0 (±7.8) years at the time of actigraphy data collection. During the follow-up period, 191 individuals converted to AD (0.2%) and 266 to PD (0.3%). After adjusting for covariates, interdaily stability, a measure of regularity, (hazard ratio [HR] per SD increase 1.24, 95% confidence interval [CI] 1.04-1.47), diurnal amplitude (HR 0.77, CI 0.64-0.93), mesor (mean activity; HR 0.73, CI 0.56-0.95), and activity during most active 10 hours (HR 0.73, CI 0.59-0.91), were each associated with an increased risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.12, CI 0.10-0.16), activity during least active 5 hours (HR 0.24, CI 0.08-0.68), and activity during most active 10 hours (HR 0.20, CI 0.16-0.25), were associated with an increased risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance. In this community-based longitudinal study, objective measures of 24-hour activity were associated with elevated risk of AD, PD, and accelerated cognitive decline, suggesting actigraphy-estimated 24-hour rhythm integrity may serve as a scalable early marker of neurodegenerative disease.
Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer
Authors: Zarei Mehrdad , Hajihassani Omid , Hue Jonathan J. , Graor Hallie J. , Rothermel Luke D. , Winter Jordan M.
Published: March 2023

Pancreatic cancer (PC) is one of the most aggressive types of cancer, with a five-year overall survival rate of 11% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with development of drug resistance. Analysis of The Cancer Genome Atlas showed that wild-type isocitrate dehydrogenase (wtIDH1) is overexpressed in pancreatic tumors. In this study, we focus on the potential roles of wtIDH1 in pancreatic cancer chemoresistance. We found that treatment of pancreatic cancer cells with chemotherapy induced expression of wtIDH1, and this serves as a key resistance factor. The enzyme is protective to cancer cells under chemotherapy-induced oxidative stress by producing NADPH and alpha-ketoglutarate to maintain redox balance and mitochondrial function. An FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtDH1 inhibitor under a nutrient-deprived microenvironment, reflective of the pancreatic cancer microenvironment. Suppression of wtIDH1 impairs redox balance, results in increased ROS levels, and enhances chemotherapy induced apoptosis in pancreatic cancer vis ROS damagein vitro.In vivoexperiments further revealed that inhibiting wtIDH1 enhances chemotherapy anti-tumor effects in patient-derived xenografts and murine models of pancreatic cancer. Pharmacologic wtIDH1 inhibition with ivosidenib represents an attractive option for combination therapies with cytotoxic chemotherapy for patients with pancreatic cancer. Based on these data, we have initiated phase Ib trial combining ivosidenib and multi-agent chemotherapy in patients with pancreatic cancer (NCT05209074).
Recent reactivation of a pathogenicity-associated transposable element triggers major chromosomal rearrangements in a fungal wheat pathogen
Authors: Badet Thomas , Feurtey Alice , Croll Daniel
Published: March 2023

Transposable elements (TEs) are key drivers of genomic variation contributing to recent adaptation in most species. Yet, the evolutionary origins and insertion dynamics within species remain poorly understood. We recapitulate the spread of the pathogenicity-associatedStyxelement across five species that last diverged ∼11,000 years ago. We show that the element likely originated in theZymoseptoriafungal pathogen genus and underwent multiple independent reactivation events. Using a global 900-genome panel of the wheat pathogenZ. tritici,we assessStyxcopy number variation and identify renewed transposition activity in Oceania and South America. We show that the element can mobilize to create additionalStyxcopies in a four-generation pedigree. Importantly, we find that new copies of the element are not affected by genomic defenses revealing a recent loss of control against the element.Styxcopies are preferentially located in recombination breakpoints and likely triggered multiple types of large chromosomal rearrangements. Taken together, we establish the origin, diversification, and reactivation of a highly active TE with major consequences for chromosomal integrity and the expression of disease.
Specific ABA-independent tomato transcriptome reprogramming under abiotic stress combination
Authors: Pardo-Hernández Miriam , Martínez-Lorente Sara E. , Martí-Guillén José M , Arbona Vicent , Simón Inmaculada , Rivero Rosa M
Published: March 2023

Crops often have to face several abiotic stresses simultaneously, and under these conditions, the plant’s response significantly differs from that observed under a single stress. Nevertheless, most of the molecular markers identified for increasing plant stress tolerance have been characterized under single abiotic stresses, explaining their unexpected results when they are tested under real field conditions. One important regulator of the plant’s responses to abiotic stresses is ABA. The ABA signaling system engages many stress-responsive genes, however, many others do not respond to ABA treatments. Thus, the ABA-independent pathway, which is still largely unknown, involve multiple signaling pathways and important molecular components necessary for the plant’s adaptation to climate change.

In the present study, tomato ABA-deficient mutants (flacca, flc) were subjected to salinity, heat, or their combination. A deep RNA-seq analysis revealed that the combination of salinity and heat induced an important reprogramming of the tomato transcriptome, and from the 685 genes that were specifically regulated under this combination in our flc mutants, 463 genes were regulated by ABA-independent systems. Among these genes, we identified 6 transcription factors (TFs) belonging to the R2R3MYB family that were significantly upregulated. A protein-protein interaction network showed that the TFs SlMYB50 and SlMYB86 were directly involved in the upregulation of the flavonol biosynthetic pathway-related genes. This is the first time that some important ABA-independent TFs involved in the specific plant response to abiotic stress combination have been identified. Considering that ABA levels dramatically change in response to environmental factors, the study of ABA-independent genes that are specifically regulated under stress combination may provide a marvelous tool for increasing plant resilience to climate change.

SIGNIFICANCE STATEMENT

This study in tomato Wt and ABA-deficient mutant plants reveals a specific and unique ABA-independent transcriptome reprogramming under abiotic stress combination, with the identification of some key TFs that were induced under these specific conditions. Taking into account that ABA levels dramatically change in all crops in response to environmental factors, the study of ABA-independent genes that are specifically regulated under stress combination may provide a marvelous tool for increasing plant resilience to climate change.
Research and optimization design of two-stage isolated inverter power supply based on series quasi-resonance
Authors: Wang Dangshu , Yi Jiaan , Song Luwen , Deng Xuan , Wang Xinxia , Dong Zhen
Published: March 2023

Purpose

This paper aims to solve the problems of large hard switching loss and unclear resonant parameter design in the existing inverter power supply topology.

Design/methodology/approach

This paper proposes a simple and reliable two-stage isolated inverter composed of series quasi-resonant push-pull and external freewheeling diode full-bridge inverter. The power supply topology is analyzed, the topology mode is analyzed, the mathematical model of the converter is established and the DC gain of the converter is deduced. The relationship between the load and the output gain of the resonant tank is presented, a new resonant parameter design method is proposed, and the parameter design of the resonant element of the converter is clarified.

Findings

The resonant components of the converter are designed according to the proposed resonant parameter design method, and the correctness of the method is verified by simulation and the development and testing of a 500 W experimental prototype. After experimental tests, the peak efficiency of the experimental prototype can reach 94%. Because the experimental prototype achieves soft switching, the heat generation of the switch is greatly reduced, so the heavy heat sink is removed, and the volume is reduced by about 30% compared with the traditional power supply, and the total harmonic distortion of the output voltage is about 2%.

Originality/value

The feasibility of the scheme is verified by experiments, which is of great significance for improving the efficiency of the inverter power supply and parameter optimization.
Efficient scale and scope of business models used in municipal solid waste management
Authors: Beccarello Massimo , Di Foggia Giacomo
Published: March 2023

Purpose

The paper aims to compare the efficiency of alternative municipal solid waste (MSW) management business models: a single provider against multiple providers.

Design/methodology/approach

In this paper the drivers of MSW management costs are analysed to test the impact of the scale and scope of MSW management services on the average cost. While the business-as-usual scenario foresees a single provider, the alternative scenario foresees multiple providers.

Findings

Based on the empirical data on municipal waste management costs, on average, the size and the average cost of the service are inversely related. This trend is supported using sub-sets defined by the quantity of waste managed. Multiple factors aid in explaining this result, and among others, due to scale and scope, factors such as transition costs increase with the number of players running different services.

Practical implications

The provision of public services of economic interest should favour the participation of more companies wherever possible to the extent that social surplus is produced. However, pursuing this principle to the detriment of efficient service delivery is not ideal. This paper demonstrated that a single-provider waste management business model is efficient under specific conditions, as in this article.

Originality/value

This paper presents an original research methodology for comparatively analysing waste management service efficiency in urban areas and provides adequate evidence using alternative measures of costs according to the phase of the waste management chain, the scale and ultimately the scope of MSW management services.
Impacts of supply chain integration on product- and service-oriented mass customisation capability: the role of customer need
Authors: Yang Qian , Geng Ruoqi , Feng Taiwen , Li Tianxiong
Published: March 2023

Purpose

This study aimed to investigate how different supply chain integrations (SCIs) (i.e. information integration and organisational integration) would impact product- and service-oriented mass customisation capability (MCC) differently and the moderating role of characteristics of customer needs (i.e. customer need tacitness and diversity).

Design/methodology/approach

From the perspective of information processing theory (IPT), the authors tested the hypotheses using survey data from 277 Chinese manufacturers.

Findings

The findings indicate that both information and operational integration contribute to product- and service-oriented MCCs. Operational integration promotes product-oriented MCC more, whereas information integration has a greater impact on service-oriented MCC. In addition, customer need tacitness negatively moderates the impact of operational integration on both product- and service-oriented MCC. Customer need diversity negatively moderates only the impact of operational integration on service-oriented MCC.

Practical implications

Managers should focus on not only the position (internal or external) but also the function of SCI when making decisions towards enhancing MCC. Diverse abilities to integrate with different functions are associated with different MCCs.

Originality/value

This study distinguishes between product- and service-oriented MCCs and provides novel insights for understanding how to enhance MCC from a SCI perspective.