bluuebunny/crossref_metadata_2025 huggingface dataset:
505 - Once-daily roflumilast cream 0.15% for atopic dermatitis: pooled results from INTEGUMENT-1/2 phase 3 trials
Authors: Eichenfield Lawrence F , Boguniewicz Mark , Simpson Eric L , Blauvelt Andrew , Gooderham Melinda , Lain Edward , Chu David H , Higham Robert C
Published: February 2024

Introduction

Roflumilast cream 0.15% is a selective, highly potent phosphodiesterase 4 inhibitor under investigation as a non-steroidal, once-daily treatment for atopic dermatitis (AD).

Objectives

Here, pooled results from two identical Phase 3 randomized controlled trials (INTEGUMENT-1: NCT04773587 and INTEGUMENT-2: NCT04773600) are presented.

Methods

Patients with AD aged ≥6 years with baseline Eczema Area and Severity Index (EASI) score ≥5 and Validated Investigator Global Assessment-AD (vIGA-AD) score of Mild or Moderate were randomized 2:1 to apply roflumilast (n=884) or vehicle (n=453) once daily for 4 weeks.

Results

A significantly greater percentage of roflumilast- versus vehicle-treated patients achieved the primary endpoint, vIGA-AD Success (Clear or Almost Clear vIGA-AD plus ≥2-grade improvement from baseline) at Week 4 (31.3% vs. 14.1%; P<0.0001). Significant differences favoring roflumilast were observed for multiple secondary endpoints at Week 4: percentage of patients achieving vIGA-AD of Clear or Almost Clear (41.1% vs. 21.4%; P<0.0001), percentage achieving 75% reduction in EASI (42.7% vs. 20.6%; P<0.0001), and percentage with baseline Worst Itch-Numeric Rating Scale ≥4 achieving a 4-point reduction (31.9% vs. 16.6%; P<0.0001). Improvement in itch was reported as early as 24 hours. Both groups had low incidences of treatment-emergent adverse events (TEAE), serious adverse events, and TEAEs leading to discontinuation. Local tolerability was favorable, with >90% of patients reporting no or mild sensation across both treatment groups at all timepoints.

Conclusions

Once-daily roflumilast cream 0.15% provided improvement across multiple efficacy endpoints by Week 4 with favorable safety and tolerability in patients aged ≥6 years with AD in two Phase 3 trials.
506 - Dupilumab is efficacious in patients with prurigo nodularis regardless of history of atopic comorbidities: pooled results from two phase 3 trials (LIBERTY-PN PRIME and PRIME2)
Authors: Kim Brian S , Gonçalo Margarida , Ugajin Tsukasa , Praestgaard Amy , Makhija Melanie , Zahn Joseph , Bansal Ashish , Wiggins Simmi
Published: February 2024

Introduction

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by severely itchy skin nodules. Nearly half of affected adult patients have a history of (or current) atopic comorbidity, such as atopic dermatitis (AD).

Objective

To report the efficacy and safety of dupilumab in patients with PN with or without history of atopic comorbidities, in a pre-specified analysis of pooled data from two phase 3 trials.

Method

In the randomized, double-blind, placebo-controlled, 24-week studies, LIBERTY-PN PRIME (NCT04183335) and PRIME2 (NCT04202679), adults with PN inadequately controlled by topical prescription therapies, were randomized 1:1 to dupilumab 300 mg every 2 weeks or matched placebo. Atopic patients were defined as patients with a physician-documented history, or current diagnosis, of at least one of the following atopic comorbidities: AD, allergic rhinitis/rhinoconjunctivitis, asthma, or food allergy. Efficacy was assessed from baseline to Week 24 through the Worst Itch Numerical Rating Scale (WI-NRS; 0–10), and the Investigator’s Global Assessment for PN-Stage score (IGA PN-S; 0–4).

Results

311 patients were randomized (dupilumab n=153, atopic/non-atopic N=67/86; placebo n=158, atopic/non-atopic N=68/90). At Week 24, significantly more atopic and non-atopic dupilumab-treated patients achieved a ≥4-point improvement in WI-NRS (58.2%/59.3%), and an IGA PN-S score of 0 or 1 (52.2%/41.9%) vs placebo (20.6%/17.8% [nominal P<0.0001/P<0.0001] and 16.2%/17.8% [nominal P<0.0001/P=0.0005], respectively). The proportion of patients achieving concomitant ≥4-point improvement in WI-NRS and IGA PN-S score of 0 or 1 was higher for both dupilumab-treated atopic and non-atopic patients (37.3%/33.7%) vs placebo (7.4%/10.0% [nominal P=0.0057/P<0.007]). Overall safety was consistent with the known dupilumab safety profile, with no remarkable differences between atopic and non-atopic patients.

Conclusion

Dupilumab treatment improves itch and skin lesions in PN patients with and without a history of atopic comorbidities, indicating that underlying type 2 inflammation is present in patients with PN regardless of their history of atopic comorbidities.
535 - Exploring the Intersectionality of Being Deaf and Black while Accessing Dermatological Care
Authors: Guy Diamond , Rotoli Jason M
Published: February 2024

In 2021, Deaf or hard of hearing (DHH) persons made up ∼3.4% of the United States population however, there was no sub-categorical data about race. This dearth of data makes it challenging to quantify the health disparities amongst Black DHH individuals. This paper aims to identify trends and disparities to improve health outcomes for DHH and Black patients seeking dermatologic care. Black patients utilize less preventative service, have lower post-trauma survival, and a 3-fold higher risk of maternal mortality than White patients. DHH patients experience delayed cancer treatment, more emergency department visits, and higher intimate partner violence than hearing patients. Black DHH patients have a higher likelihood of cancer, diabetes, hypertension, and lung disease than Black-hearing patients. Black patients have lower survival rates with certain cutaneous neoplasms and poorer disease control than White counterparts. The literature lacks dermatologic care outcomes for Black DHH patients.

Shared themes impacting Black and DHH patients’ care include audism and racism, medical mistrust, and poor communication with clinicians. Unfortunately, the dermatological experiences of Black DHH patients are poorly documented. To minimize disparities for this population, clinicians must acknowledge them and partner with the community to investigate them.
557 - Tralokinumab real-world use in adults with atopic dermatitis: baseline characteristics of the first 100 patients recruited to the TRACE study in the United States
Authors: Armstrong April W , Rubin Cory , Jarell Abel , Nguyen Tien , Bagel Jerry , Stinson John , Schneider Shannon , Anastasiadou Dimitra M , Rodriguez Adrian
Published: February 2024

Introduction/Background

Tralokinumab is a fully human, high-affinity, monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD) pathogenesis. Numerous clinical studies have established that tralokinumab is an efficacious treatment for patients with moderate-to-severe AD, along with having a favorable safety profile. However, there is a lack of evidence on tralokinumab use in routine clinical practice, where patient management may differ from that defined by clinical trial protocols.

Objectives

TRACE is a global, real-world study that aims to better understand the effectiveness, safety, and clinical use of tralokinumab in patients with AD in daily practice.

Methods

TRACE is a global, observational, prospective, single-cohort study of tralokinumab-treated adults with moderate-to-severe AD. Overall, 11 countries across Europe, North America and the Middle East are participating. The primary objective of TRACE is to assess changes in clinical signs and symptoms of AD in patients treated with tralokinumab according to the nationally approved labels. Secondary objectives include safety, quality of life, patient-reported outcomes and treatment adherence. For this interim analysis, the objective was to report the baseline characteristics of the first 100 US patients.

Results

Overall, 55% of the first 100 US patients initiated on tralokinumab in the TRACE study were female; the majority (54%) were White, followed by 18% Black or African American and 12% Asian. Mean (standard deviation [SD]) age was 46.4 years (18.2) and body mass index was 28.6 kg/m2 (7.7). Patients had a mean disease duration of 13.9 years (SD 16.5), with 46% being biologic-naïve and 54% biologic-experienced. Most patients (88%) had moderate-to-severe AD, with a mean Investigator’s Global Assessment score of 3.2 (SD 0.8); mean Eczema Area and Severity Index was 15.4 (SD 7.9). A heavy symptomatic burden of disease was evident, with a mean eczema-related sleep numerical rating scale (NRS) of 4.2 (SD 3.3) and mean worst daily pruritus NRS of 6.1 (SD 2.6). Patients also reported a substantial impact of AD on quality of life; mean Dermatology Life Quality Index was 13.2 (SD 8.5). Almost one quarter (24%) of patients reported ≥1 atopic comorbidity, with asthma (12%), cardiovascular disease (8%) and autoimmune disease (6%) being the most frequent; 3% of patients had psychiatric illness.

Conclusions

Initial findings showed that tralokinumab is being prescribed as a first-line biologic treatment option in the US in accordance with the label. Treated patients had a heavy burden of disease with considerable impact on quality of life.
561 - Dupilumab treatment reduces signs in patients with atopic hand and foot dermatitis: results from a phase 3, randomized, double-blind, placebo-controlled trial
Authors: Simpson Eric L , Soong Weily , Worm Margitta , Pinter Andreas , Masuda Koji , Shao Liyang , Dubost-Brama Ariane , Bansal Ashish , Korotzer Andrew , Rossi Ana B
Published: February 2024

Introduction/Background

Dupilumab has previously shown overall efficacy in treating atopic hand and foot dermatitis.

Objective

To report the effect of dupilumab treatment on individual signs of atopic hand and foot dermatitis.

Methods

The phase 3, randomized, double-blind LIBERTY-AD-HAFT (NCT04417894) trial enrolled patients aged ≥12 years with moderate-to-severe (Investigator’s Global Assessment [IGA] score of 3/4) atopic hand and foot dermatitis. Patients were randomized to dupilumab monotherapy 300 mg every 2 weeks (q2w) in adults; 200/300 mg q2w in adolescents, or placebo for 16 weeks. This analysis presents the proportion of patients reporting absent, mild, moderate, or severe erythema, scaling/flaking, lichenification, vesiculation/erosion, edema, and fissures, assessed by the modified total lesion sign score (mTLSS) in hands and feet.

Results

At baseline, most patients had scores of moderate or severe signs on their hands. Of the 133 patients enrolled, over 65% of patients treated with dupilumab (n = 67) achieved an absent or mild score by Week 16 in each of the signs/symptoms assessed. Proportion of patients with absent or mild hand scores increased from baseline to Week 16 in erythema (9% vs 71.6%), scaling/flaking (16.4% vs 74.7%), lichenification (4.5% vs 65.6%), vesiculation/erosion (43.3% vs 89.6%), edema (44.7% vs 86.6%), and fissures (23.9% vs 83.5%). Proportion of patients with absent or mild foot scores increased from baseline to Week 16 in erythema (56.7% vs 80.6%), scaling/flaking (56.7% vs 82.1%), lichenification (53.8% vs 82.1%), vesiculation/erosion (76.1% vs 86.6%), edema (76.1% vs 88.1%), and fissures (77.6% vs 86.6%). Safety was consistent with the known dupilumab safety profile in patients with atopic dermatitis.

Conclusions

Dupilumab treatment in patients improves signs of hand and foot dermatitis, including erythema, scaling/flaking, lichenification, vesiculation/erosion, edema, and fissures.
568 - Persistent inadequate disease control and therapeutic inertia in moderate-to-severe atopic dermatitis: a 12-month longitudinal analysis of real-world outcomes from TARGET-DERM registry
Authors: Eichenfield Lawrence F , Grada Ayman , Knapp Keith D , Munoz Breda , Crawford Julie M , Silverberg Jonathan I
Published: February 2024

Background

Therapeutic inertia refers to the delay or failure to escalate treatment in patients who are not achieving adequate disease control and poses a challenge in the management of moderate-to-severe atopic dermatitis (AD). Despite the availability of conventional (CST) and advanced systemic therapies (AST) currently utilized for the treatment of moderate to severe AD, many patients do not achieve treatment success. However, the extent of this inadequacy in real-world clinical practice remains underexplored.

Objectives

This study aims to evaluate the occurrence therapeutic inertia (assessed as non-escalation of therapy despite limited disease control) and the proportion of patients with moderate-to-severe AD who continue to show an inadequate response after receiving systemic therapies for a duration ranging from 3 to 12 months.

Methods

We conducted a longitudinal analysis of patients with moderate-to-severe AD (vIGA-AD≥3) from the TARGET-DERM AD registry, including 3,457 participants from 39 centers in the U.S. and Canada. Eligible patients had documented outcomes at the initiation of systemic therapy and after 3 months up to 12 months of follow up. We assessed clinician- and patient-reported outcomes to identify the proportion of patients not meeting pre-defined targets based on expert consensus. An inadequate response was defined as not achieving a validated Investigator Global Assessment (vIGA-AD) score ≤2, a 50% improvement in Body Surface Area (BSA), and a ≥4-point reduction in the Worst Pruritus Numeric Rating Scale (WP-NRS). An optimal response was defined as a vIGA-AD score ≤1 (clear or almost clear skin), BSA ≤2%, and WP-NRS itch score of 0/1 (complete or almost complete skin resolution).

Results

Out of 2,107 patients with moderate-to-severe AD, 445 met the inclusion criteria. The majority were adults (63.8%), female (62.0%), and Non-Hispanic White (45.4%), with an average age of 31 years. Most patients (88.8%) initiated treatment with AST, with dupilumab being the most common (86.5%). The mean vIGA-AD was 3.3 for AST and 3.6 for CST at initiation (P<0.01). At 6 months, 37% and 67% of AST-treated patients had inadequate responses in terms of skin clearance and itch outcomes, respectively, while 82% and 79% did not achieve optimal responses. At 12 months, these figures were approximately 30% and 66% for inadequate responses and 85% and 88% for not achieving optimal responses, respectively. CST-treated patients showed a similar trend.

Conclusions

The study reveals a significant portion of moderate-to-severe AD patients fail to achieve adequate disease control with systemic therapies over 12 months, indicating a substantial presence of therapeutic inertia. These findings suggest a need for more proactive management strategies in AD treatment.
550 - Vitiligo is associated with new onset osteoporosis: a population-based study
Authors: Cohen Naama Tova , Silverberg Nanette B , Kridin Khalaf
Published: February 2024

Introduction/Background

Vitiligo, an autoimmune disease leading to skin depigmentation, affects about 2% of the global population. The current pathogenesis for vitiligo is the autoimmune theory; recent reports demonstrated the role of pro-inflammatory cytokines in vitiligo. Osteoporosis is an inflammatory condition, characterized by elevated pro-inflammatory cytokines, associated with increased bone metabolism. The association between osteoporosis and vitiligo has never been investigated in a cohort study. We aimed to investigate if patients with vitiligo are at increased risk for developing osteoporosis.

Methods

A retrospective, cohort study was conducted on the Clalit Health Services (CHS) database (2002-2019) exploring age, sex, ethnicity, comorbidities, and Charlson comorbidity index.

Results

19,985 vitiligo patients, and 99,003 controls, mean age 33.2 (SD +/-21.6) years were included. The incidence rates (95%CI) of new-onset osteoporosis were 2.6 (2.3-2.9)/1,000 person-years (PY) in vitiligo patients and 2.2 (2.1-2.3)/1,000PY in the control group. In multivariate analysis adjusted for age, sex, ethnicity, smoking, obesity, hyperlipidemia, diabetes mellitus, and hypertension, the hazard ratio (95% CI) for new-onset osteoporosis in patients with vitiligo was 1.19 (1.04-1.38, p-value 0.006). In vitiligo patients, the odds ratio (95%CI) for osteoporosis were 2.05 (1.91-2.21, p-value <0.001), female sex 4.04 (3.03-5.38, p-value 0.001), Jewish ethnicity 3.65 (2.45-5.44, p-value <0.001), hypertension 5.02 (3.96-6.36, p-value <0.001), hyperlipidemia 6.99 (5.37-9.08, p-value <0.001), obesity 1.34 (1.02-1.76, p-value-0.036) and diabetes mellitus 3.56 (2.74-4.62, p-value <0.001).

Conclusions

In the current study we observed an increased risk of developing osteoporosis in patients with vitiligo. Our observation merits further study and highlights the systemic aspect of inflammation in vitiligo.
The role of place in the development of a circular economy: a critical analysis of potential for social redistribution in Hull, UK
Authors: Deutz Pauline , Jonas Andrew E G , Newsholme Aodhan , Pusz Małgorzata , Rogers Heather A , Affolderbach Julia , Baumgartner Rupert J , Ramos Tomás B
Published: February 2024

This paper examines the role of place in the local development of a circular economy and the potential for consequent social redistribution. Based on a case study of public, private and third-sector approaches to a circular economy in Hull, an industrial city in the northeast of England, it offers a critical analysis of the geographic distribution of socio-economic benefits from local circular economy developments. Policy goals of inclusivity (or a ‘just transition’) are not accomplished. However, attachment to place provides opportunities to bridge sectoral and jurisdictional boundaries and potentially generate more socially inclusive territorial-distributional outcomes.
Management of de novo nephrolithiasis after kidney transplantation: a comprehensive review from the European Renal Association CKD-MBD working group
Authors: Kanbay Mehmet , Copur Sidar , Bakir Cicek N , Hatipoglu Alper , Sinha Smeeta , Haarhaus Mathias
Published: February 2024

The lifetime incidence of kidney stones is 6%–12% in the general population. Nephrolithiasis is a known cause of acute and chronic kidney injury, mediated via obstructive uropathy or crystal-induced nephropathy, and several modifiable and non-modifiable genetic and lifestyle causes have been described. Evidence for epidemiology and management of nephrolithiasis after kidney transplantation is limited by a low number of publications, small study sizes and short observational periods. Denervation of the kidney and ureter graft greatly reduces symptomatology of kidney stones in transplant recipients, which may contribute to a considerable underdiagnosis. Thus, reported prevalence rates of 1%–2% after kidney transplantation and the lack of adverse effects on allograft function and survival should be interpreted with caution. In this narrative review we summarize current state-of-the-art knowledge regarding epidemiology, clinical presentation, diagnosis, prevention and therapy of nephrolithiasis after kidney transplantation, including management of asymptomatic stone disease in kidney donors. Our aim is to strengthen clinical nephrologists who treat kidney transplant recipients in informed decision-making regarding management of kidney stones. Available evidence, supporting both surgical and medical treatment and prevention of kidney stones, is presented and critically discussed. The specific anatomy of the transplanted kidney and urinary tract requires deviation from established interventional approaches for nephrolithiasis in native kidneys. Also, pharmacological and lifestyle changes may need adaptation to the specific situation of kidney transplant recipients. Finally, we point out current knowledge gaps and the need for additional evidence from future studies.
GWAS supported by computer vision identifies large numbers of candidate regulators of in planta regeneration in Populus trichocarpa
Authors: Nagle Michael F , Yuan Jialin , Kaur Damanpreet , Ma Cathleen , Peremyslova Ekaterina , Jiang Yuan , Niño de Rivera Alexa , Jawdy Sara , Chen Jin-Gui , Feng Kai , Yates Timothy B , Tuskan Gerald A , Muchero Wellington , Fuxin Li , Strauss Steven H
Published: February 2024

Plant regeneration is an important dimension of plant propagation and a key step in the production of transgenic plants. However, regeneration capacity varies widely among genotypes and species, the molecular basis of which is largely unknown. Association mapping methods such as genome-wide association studies (GWAS) have long demonstrated abilities to help uncover the genetic basis of trait variation in plants; however, the performance of these methods depends on the accuracy and scale of phenotyping. To enable a large-scale GWAS of in planta callus and shoot regeneration in the model tree Populus, we developed a phenomics workflow involving semantic segmentation to quantify regenerating plant tissues over time. We found that the resulting statistics were of highly non-normal distributions, and thus employed transformations or permutations to avoid violating assumptions of linear models used in GWAS. We report over 200 statistically supported quantitative trait loci (QTLs), with genes encompassing or near to top QTLs including regulators of cell adhesion, stress signaling, and hormone signaling pathways, as well as other diverse functions. Our results encourage models of hormonal signaling during plant regeneration to consider keystone roles of stress-related signaling (e.g. involving jasmonates and salicylic acid), in addition to the auxin and cytokinin pathways commonly considered. The putative regulatory genes and biological processes we identified provide new insights into the biological complexity of plant regeneration, and may serve as new reagents for improving regeneration and transformation of recalcitrant genotypes and species.
Climate change and peacebuilding: sub-themes of an emerging research agenda
Authors: Krampe Florian , O'Driscoll Dylan , Johnson McKenzie , Simangan Dahlia , Hegazi Farah , de Coning Cedric
Published: February 2024

Climate change is having profound effects on global security and peacebuilding efforts. While existing research has mainly focused on the link between climate change and conflict, it has largely overlooked the complex interplay between climate change, conflict-affected states and peacebuilding. Climate change exacerbates existing vulnerabilities in conflict-affected societies by adding stress to livelihoods and negatively impacting food, water and energy security. This is particularly concerning as climate change is often felt most acutely in settings where public institutions are already failing to meet the population's needs. Consequently, climate change can contribute to exacerbating grievances and hinder the ability to maintain, reinforce and build peace. Although practitioners in the peacebuilding field are beginning to respond to the effects of climate change, academic research has not adequately addressed the question of how climate change affects peacebuilding and how peacebuilding strategies can respond effectively. To fill this gap, a multidisciplinary approach drawing from climate security, environmental peacebuilding, environmental studies, and peace and conflict studies is needed in order to develop a research agenda that encompasses the intersections of climate change and peacebuilding. By recognizing the importance of climate change in peacebuilding efforts, this research agenda aims to provide critical insights and guide future studies.
From imperial power to regional policeman: Ethiopian peacekeeping and the developmental state
Authors: Verhoeven Harry , Gebregziabher Tefera Negash
Published: February 2024

Why and how do African states become peacekeepers? Through a single-case study, this article accounts for a transformation in peace and security: how Ethiopia became the world's prime source of blue helmets in the early twenty-first century, having largely shunned peacekeeping in preceding decades. We propose that peacekeeping came to serve as an unexpectedly useful technology to pursue state-building agendas. Historically, regional proxy wars undermined state-building efforts in Ethiopia and mismanagement of ethno-linguistic diversity rendered it vulnerable to externally supported rebellions. In the 2000s, an evolving approach to peacekeeping dovetailed with the ruling Ethiopian People's Revolutionary Democratic Front's (EPRDF) vision for recalibrating political order domestically and in the Horn of Africa. EPRDF became convinced that changing Ethiopia required changing its surrounding region. Regional intervention as peacekeeping was supported by global powers and helped bind neighbouring states to Ethiopia in new ways. This entailed the crafting of deep political ties in Somalia, South Sudan and Sudan that mitigated historical fears of Ethiopian hegemony and shielded EPRDF state-building from outside destabilization. Moreover, as Ethiopia's increasingly prominent role in United Nations and African Union missions improved the external environment for the EPRDF developmental state, it also expanded Ethiopian National Defence Force's role in the political economy, buttressing the party-state's hegemony.
Pressure and convection robust bounds for continuous interior penalty divergence-free finite element methods for the incompressible Navier–Stokes equations
Authors: García-Archilla Bosco , Novo Julia
Published: February 2024

In this paper, we analyze a pressure-robust method based on divergence-free mixed finite element methods with continuous interior penalty stabilization. The main goal is to prove an $O(h^{k+1/2})$ error estimate for the $L^2$ norm of the velocity in the convection dominated regime. This bound is pressure robust (the error bound of the velocity does not depend on the pressure) and also convection robust (the constants in the error bounds are independent of the Reynolds number).
Romosozumab added to ongoing denosumab in postmenopausal osteoporosis, a prospective observational study
Authors: Adami Giovanni , Pedrollo Elisa , Rossini Maurizio , Fassio Angelo , Braga Vania , Pasetto Emma , Pollastri Francesco , Benini Camilla , Viapiana Ombretta , Gatti Davide
Published: February 2024

Background

Optimization of sequential and combination treatment is crucial in shaping long-term management of postmenopausal osteoporosis (OP).

Methods

We conducted a 6-month prospective observational study on postmenopausal women with severe OP receiving treatment with romosozumab either alone (in patients naïve to treatment) or in combination with ongoing long-term denosumab (>2 years) or continuing ongoing denosumab alone (>2 years). We collected serum samples for bone turnover markers, bone modulators, and calcium phosphate metabolism at baseline, month 3 and month 6. BMD was assessed at baseline and after 6 months.

Results

Fifty-two postmenopausal women with OP were included in the study. Nineteen received romosozumab alone, 11 received romosozumab combined to ongoing denosumab, and 22 continued denosumab alone. BMD increased significantly at all sites at 6 months of follow-up in the romosozumab alone group (femoral neck +8.1%, total hip +6.8%, and lumbar spine +7.9%). In contrast, BMD increased significantly only at lumbar spine in the combination group (+7.2%) and in the denosumab group (+1.5%). P1nP increased significantly in romosozumab groups at month 3 (+70.4% in romosozumab alone group and +99.1% in combination group). Sclerostin levels increased steeply in both romosozumab groups, and Dkk1 did not change.

Conclusion

Romosozumab added to ongoing denosumab resulted in an increase in P1nP and lumbar spine BMD, but not in femoral neck BMD. For patients on denosumab, using romosozumab as an additional treatment appeared to be useful in terms of bone formation markers and spine BMD vs denosumab alone. Further randomized controlled trials, possibly powered to fracture outcomes, are needed to confirm our results.
Glandular doses and diagnostic reference levels (DRLs) for Saudi breast cancer screening programme (2012–2021)
Authors: Albeshan Salman M , Alhulail Ahmad A , Almuqbil Maha M
Published: February 2024

The aim of this study was to report the diagnostic reference levels (DRLs) corresponding to different compressed breast thickness (CBT) ranges. To achieve this, mammographic examinations with 187,788 exposures were analysed. The mean average glandular (AGD) dose was calculated per view, examination, and center. Moreover, the DRL values corresponding to different CBT ranges were reported. The result of the mean AGD per view was found to be 1.36 mGy for craniocaudal (CC) and 1.54 mGy for Mediolateral oblique (MLO), while the mean AGD per examination for all women was 1.45 mGy. The DRL values corresponding to CBTs between 20 to 79 mm ranges were below 2 mGy. These results were from a population of mean age = 49 ± 8 years and mean CBT = 58 ± 8 mm, and was imaged with mean exposures of 29 ± 1 kVp and 74 ± 31 mAs, and a mean compression force of 135±37 N. In conclusion, good mammography practice has been shown, as DRL values are within the limits suggested by the international organizations.
Measurement of Hp(10), Hp(3) and Hp(0.07) to medical staff in endoscopic retrograde cholangiopancreatography, using thermoluminescence dosimetry
Authors: ZarifSanayei Ava , Sina Sedigheh
Published: February 2024

Endoscopic retrograde cholangiopancreatography (ERCP) is widely used in the diagnosis and treatment of pancreatic and bile duct disorders. The procedure is performed under the guidance of fluoroscopy. This study aims to investigate the dose received by staff in the Endoscopy Department of AbuAli Sina Medicine and Organ Transplant Hospital in Shiraz. The dosimetry was performed using thermoluminescent dosemeters (TLD), type TLD-100. The values of Hp(10), Hp(3) and Hp(0.07) were estimated for the staff for 2 months. According to the results obtained in this study, the equivalent dose of the gastroenterologist’s body, eye lenses and hands was 0.045 ± 0.001 mSv, 0.111 ± 0.014 mSv and 0.357 ± 0.034 $\mathrm{mSv}$, respectively. This study showed that the annual radiation exposure for ERCP department staff of Abu Ali Sinai Hospital is less than the annual dose limit. However, if the principles of proper radiation protection and individual dosimetry are followed, the dose to staff members can be reduced.
Teaching schools to compete: the case of Swedish upper secondary education
Authors: Arora-Jonsson Stefan , Edlund Peter
Published: February 2024

Significant efforts have been made to promote competition in public service sectors, expanding the reach of competition into non-economic fields. Surprisingly little is, however, known about the process by which competition is introduced into such settings. We examine this process, focusing on a Swedish municipality’s efforts to implement competition for students among its schools. By incorporating recent theoretical advancements regarding competition as an organized relationship, and utilizing a combination of qualitative and quantitative data, we shed light on the organizational efforts undertaken by politicians and bureaucrats to teach their schools to compete. We find that introducing competition can be complex, time-consuming and that it requires substantial organizational commitment. We highlight the existence of varying perceptions of competition among different stakeholders following its introduction. These findings suggest the need for future research that addresses questions about the costs of, and interests behind, introducing competition, as well as questions about responsibility for the subsequent effects of competition.
Prisons and Pollution: A Nationwide Analysis of Carceral Environmental Inequality
Authors: Greenberg Pierce , Perdue Robert Todd
Published: February 2024

The disproportionate exposure of incarcerated populations to environmental harms is an emerging area of interest among scholars and activists. Existing research has illuminated these intersecting systems of inequality with broad theorization and case study examples of prisons and jails located near environmental hazards. However, there are few nationwide assessments of carceral environmental inequality—studies examining whether prison communities in the United States are disproportionately located near environmental harms. Our paper examines the influence of prison proximity on four measures of environmental harm to test whether carceral environmental inequality exists in the United States at the census tract level. Multi-level regression models—which account for the nested nature of census tracts within both counties and states—find that (1) closer proximity to a prison is associated with higher levels of pollution across all measures of environmental harm, and (2) that trend is mostly driven by proximity to county jails rather than state or federal prisons. We suggest that these trends may be driven by complex prison and pollution siting patterns. Our paper concludes by discussing the implications of these findings for future research on carceral environmental inequality.
Assessing the mitochondrial safety profile of the molnupiravir active metabolite, β-d-N4-hydroxycytidine (NHC), in the physiologically relevant HepaRG model
Authors: Kiy Robyn T , Khoo Saye H , Chadwick Amy E
Published: February 2024

Background

β-d-N4-Hydroxycytidine (NHC) is the active metabolite of molnupiravir, a broad-spectrum antiviral approved by the MHRA for COVID-19 treatment. NHC induces lethal mutagenesis of the SARS-CoV-2 virus, undergoing incorporation into the viral genome and arresting viral replication. It has previously been reported that several nucleoside analogues elicit off-target inhibition of mitochondrial DNA (mtDNA) or RNA replication. Although NHC does not exert these effects in HepG2 cells, HepaRG are proven to be advantageous over HepG2 for modelling nucleoside analogue-induced mitochondrial dysfunction. Therefore, the objective of this work was to assess the mitotoxic potential of NHC in HepaRG cells, a model more closely resembling physiological human liver.

Methods

Differentiated HepaRG cells were exposed to 1–60 μM NHC for 3–14 days to investigate effects of sub-, supra-, and clinically-relevant exposures (in the UK, molnupiravir for COVID-19 is indicated for 5 days and reported Cmax is 16 μM). Following drug incubation, cell viability, mtDNA copy number, mitochondrial protein expression, and mitochondrial respiration were assessed.

Results

NHC induced minor decreases in cell viability at clinically relevant exposures, but did not decrease mitochondrial protein expression. The effects on mtDNA were variable, but typically copy number was increased. At supra-clinical concentrations (60 μM), NHC reduced mitochondrial respiration, but did not appear to induce direct electron transport chain dysfunction.

Conclusions

Overall, NHC does not cause direct mitochondrial toxicity in HepaRG cells at clinically relevant concentrations, but may induce minor cellular perturbations. As HepaRG cells have increased physiological relevance, these findings provide additional assurance of the mitochondrial safety profile of NHC.
G‐protein‐coupled estrogen receptor 1 promotes peritoneal metastasis of gastric cancer through nicotinamide adenine dinucleotide kinase 1‐mediated redox modulation
Authors: Wu Teng , Ding Ke , Wang Chun , Lin Guoliang , Xie Chengjie , Chen Xianying , Li Quanxin , Yu Fenghai , Mao Yuling , Hong Wei , Lu Lei , Li Shuai
Published: February 2024

Adipose tissue is the second most important site of estrogen production, where androgens are converted into estrogen by aromatase. While gastric cancer patients often develop adipocyte‐rich peritoneal metastasis, the underlying mechanism remains unclear. In this study, we identified the G‐protein‐coupled estrogen receptor (GPER1) as a promoter of gastric cancer peritoneal metastasis. Functional in vitro studies revealed that β‐Estradiol (E2) or the GPER1 agonist G1 inhibited anoikis in gastric cancer cells. Additionally, genetic overexpression or knockout of GPER1 significantly inhibited or enhanced gastric cancer cell anoikis in vitro and peritoneal metastasis in vivo, respectively. Mechanically, GPER1 knockout disrupted the NADPH pool and increased reactive oxygen species (ROS) generation. Conversely, overexpression of GPER1 had the opposite effects. GPER1 suppressed nicotinamide adenine dinucleotide kinase 1(NADK1) ubiquitination and promoted its phosphorylation, which were responsible for the elevated expression of NADK1 at protein levels and activity, respectively. Moreover, genetic inhibition of NADK1 disrupted NADPH and redox homeostasis, leading to high levels of ROS and significant anoikis, which inhibited lung and peritoneal metastasis in cell‐based xenograft models. In summary, our study suggests that inhibiting GPER1‐mediated NADK1 activity and its ubiquitination may be a promising therapeutic strategy for peritoneal metastasis of gastric cancer.
Cardiopulmonary Resuscitation Education in United States Schools: Shortcomings and Future Directions
Authors: Whiteson Harris Z. , Weiss Matthew B. , Frishman William H.
Published: February 2024

Cardiopulmonary resuscitation (CPR) is a lifesaving procedure that is performed during a cardiac arrest. CPR consists of chest compressions, rescue breaths, and the usage of an automated external defibrillator (AED) based on availability. Performance of CPR can greatly increase the chances of survival by enabling the manual perfusion of vital organs in lieu of the heart’s normal function. Despite extensive studies demonstrating the efficacy and necessity of CPR in an emergency, most of the public across the United States is ill-equipped and/or educated on how to perform it. While there may be other contributing factors, the lack of CPR education across schools in the United States almost certainly furthers the CPR illiteracy of the general population. Although states require some degree of CPR training, the level of education that students receive varies widely across communities and school districts, largely dictated by the available funding for training courses. Despite the lack of CPR education in the United States, studies conducted abroad have shown the efficacy of a CPR course in preparing students to respond in emergencies–lending hope to mending the current situation in the United States. In this article, we analyze legislation dictating CPR instruction and hypothesize ways in which states’ Department of Education might be able to promote education and hands-on experience for students across all ages of schooling. Ultimately, we hope to highlight the importance and feasibility of preparing the next generation of citizens across the United States to respond when their name is called upon in an emergency.
Barriers and facilitators to physical activity participation among community-dwelling physically inactive individuals after stroke: a qualitative exploratory study
Authors: Karadag-Saygi Evrim , Giray Esra , Eren Nurullah , Yolcu Gunay , Coskun Ozge Kenis , Cifcili Serap
Published: February 2024

Physical activity has been shown to reduce the risk for first-ever stroke as well as recurrent stroke with positive effects on almost all known modifiable risk factors. However, the perceived barriers and facilitators for engaging in physical activity have been insufficiently studied and may differ between cultures. Therefore, the aim of this study was to explore the perceptions of community-dwelling physically inactive individuals with stroke about barriers and facilitators to their participation in physical activity. This qualitative study included two focus groups of ten individuals with stroke classified as physically inactive based on accelerometer recordings. A semi-structured set of questions was posed in each focus group session and the transcripts were analysed using thematic analysis. The results revealed three main themes and subthemes: individual factors (physical impairments, psychological factors, spirituality), interaction with the family (attitudes of family members/close community) and social and environmental factors (hobbies, lack of or presence of facilities, the use of orthosis). We conclude that physical activity participation is affected by a multitude of factors as well as cultural differences. Thus, interventions aimed at increasing participation in physical activity after stroke should not only be planned according to individual clinical characteristics but also take into account a range of personal-to-social factors, including cultural differences.
Correlations of 2 Novel Inflammation Indexes With the Risk for Early Neurological Deterioration in Acute Ischemic Stroke Patients After Intravenous Thrombolytic Therapy
Authors: Wang Nuo , Wang Ling , Zhang Minmin , Deng Benqiang , Wu Tao
Published: February 2024

Objectives:

Elevation of the systemic immune inflammation (SII) index and system inflammation response index (SIRI) is known to be associated with higher risk of stroke and all-cause death. However, no study has reported their correlation with early neurological deterioration (END) following recombinant tissue-type plasminogen activator (IV-rtPA) in acute ischemic stroke patients. The aim of this study was to explore the correlation of SII and SIRI with the risk of END after IV-rtPA.

Methods:

Included in this study were 466 consecutive patients treated with IV-rtPA. SII and SIRI were calculated according to blood cell counts before IV-rtPA. Patients were divided into 3 groups based on trisectional quantiles according to SII and SIRI values. The risk of END was assessed by multivariate regression. The overall discriminative ability of SII and SIRI in predicting END was assessed by receiver operating characteristic curve analysis.

Results:

Of the 466 included patients, 62 (13.3%) were identified as having END. Compared with the first tertile of SII, multivariable regression analysis demonstrated that patients were more likely to have END (odds ratio 2.54; 95% CI: 1.23-5.23) and poor outcome at 90 days (odds ratio 2.02; 95% CI: 1.06-3.86) in third tertile after adjustment for potential confounders. In addition, a cutoff value of 591.63 for SII was detected in predicting post-thrombolysis END with a sensitivity of 58.1% and a specificity of 64.6% (area under the curve 0.61; 95% CI: 0.54-0.69).

Conclusions:

Higher SII but not SIRI may prove to be a predictor for high risk of END and a poor functional outcome at 90 days after IV-rtPA.
Clinical Value of Procalcitonin as a Biomarker for Detecting a Primary Tuberculous Spinal Infection: Case Report and Review of the Literature.
Authors: Ben Lahlou Yassine , Dokponou Yao Christian Hugues , Malihy Zakaria , Benaissa Elmostapha , Maleb Adil , Elouennass Mostapha , Chadli Mariama
Published: February 2024

Procalcitonin is a biomarker, potentially useful in the diagnosis of sepsis and severe bacterial infections. Few studies have examined the usefulness of this biological marker in the diagnosis of tuberculous spondylodiscitis.
We report the case of a 37-year-old woman with an unremarkable medical history who was newly diagnosed with tuberculous spondylodiscitis while the procalcitonin test was negative. This case confirms the hypothesis that procalcitonin is not a useful parameter to support the diagnosis of primary tuberculous spondylodiscitis.
The evolutionary age-range size relationship is modulated by insularity and
dispersal in plants and animals
Authors: Alzate Adriana , Rozzi Roberto , Velasco Julian A. , Robertson D. Ross , Zizka Alexander , Tobias Joseph A. , Hill Adrian , Bacon Christine D. , Janzen Thijs , Pellissier Loïc , van der Plas Fons , Rosindell James , Onstein Renske E.
Published: February 2024

Earth is home to millions of plant and animal species, with more than 40
thousand species facing extinction worldwide (Diaz et al. 2019). Species’ range
size is particularly important in this context because it influences extinction
risk (Purvis et al. 2000, Gaston & Fuller 2009), but the causes underlying
the wide natural variation in range size remain poorly known. Here, we
investigate how evolutionary age is related to present-day range size for over
25,000 species of mammals, birds, reptiles, amphibians, reef fishes, and plants.
We show that, on average, older species have significantly larger ranges, but
the effect of age on range size is modulated by clade, geographical context and
dispersal ability. Specifically, age does not affect range size for island
species, because islands limit dispersal and hence range size, regardless of
species age. Furthermore, species from clades with high dispersal capabilities
obtain large ranges faster, thereby further neutralizing the relationship
between age and range size. Our results can help supporting global conservation
priorities, by showing that species that are young, occupy islands, and/or are
dispersal limited often have small ranges and therefore increased extinction
risk.
Environmental DNA from ethanol eluent of flowers reveals a widespread diversity in cowpea associated animal communities in Hainan Island
Authors: Chen Qi , Yu Huai-Liang , Lv Jun-Xian , Wang Xing , Li Jin , Wu Ming-Yue , Shi Cai-Hua , Xie Wen , Kong Xiang-Yi , Huang Guo-Hua
Published: February 2024

Cowpea (Vigna unguiculata(L.) Walp.), as an economical crop, is one of the important pillar industries of rural revitalization strategy in China. However, cowpea planting in China is often infested and damaged by many insects during growth, especially in Hainan region with a warm and wet tropical climate. Traditional monitoring methods with technical limitation could only detect a few common significant agricultural pests, how many kinds of species associated with cowpea is unknown. Here, we employed environmental DNA (eDNA) metabarcoding to characterize cowpea associated animal community-level diversity among six planting areas in Hainan. In all, 62 species were detected, of which 99.05% was Arthropoda, suggesting that Arthropods are the main groups interacting with cowpea. Moreover, we also detected 28 pests on cowpea, predominantly belonging to Thysanoptera, Lepidoptera, Diptera and Hemiptera, of which 20 pests were first reported and need more extra attention. Furthermore, clustering results indicated that there is a certain diversity of cowpea associated animals in different regions of Hainan, but the species composition was similar in the large planting areas due to the indiscriminate use of pesticides, which need further develop scientific pesticide applications to ensure adequate species diversity. This study represents the first molecular approach to investigate the cowpea associated animal communities and provides basic information for further scientific pesticide applications.
Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair
Authors: Saul Dominik , Doolittle Madison L. , Rowsey Jennifer L. , Froemming Mitchell N. , Kosinsky Robyn L. , Vos Stephanie J. , Ruan Ming , LeBrasseur Nathan , Chandra Abhishek , Pignolo Robert , Passos João F. , Farr Joshua N. , Monroe David G. , Khosla Sundeep
Published: February 2024

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was p21+ and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells are key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings establish contextual roles of p21+vsp16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.