bluuebunny/crossref_metadata_2025 huggingface dataset:
A multicenter investigator-initiated Phase 2 trial of E7090 in patients with advanced or recurrent solid tumor with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial
Authors: Chiba Yohei , Sudo Kazuki , Kojima Yuki , Okuma Hitomi , Kohsaka Shinji , Machida Ryunosuke , Ichimura Masahiko , Anjo Kenta , Kurishita Kazumi , Okita Natsuko , Nakamura Kenichi , Kinoshita Ichiro , Takahashi Masanobu , Matsubara Junichi , Kusaba Hitoshi , Yonemori Kan , Takahashi Masamichi
Published: August 2022

Background

Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project).

Methods/Design

This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021.

Discussion

A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities.

Trial registration

Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) ClinicalTrials.gov: NCT04962867 (registered July 15, 2021).
Small-area estimation for public health surveillance using electronic health record data: reducing the impact of underrepresentation
Authors: Chen Tom , Li Wenjun , Zambarano Bob , Klompas Michael
Published: August 2022

Background

Electronic Health Record (EHR) data are increasingly being used to monitor population health on account of their timeliness, granularity, and large sample sizes. While EHR data are often sufficient to estimate disease prevalence and trends for large geographic areas, the same accuracy and precision may not carry over for smaller areas that are sparsely represented by non-random samples.

Methods

We developed small-area estimation models using a combination of EHR data drawn from MDPHnet, an EHR-based public health surveillance network in Massachusetts, the American Community Survey, and state hospitalization data. We estimated municipality-specific prevalence rates of asthma, diabetes, hypertension, obesity, and smoking in each of the 351 municipalities in Massachusetts in 2016. Models were compared against Behavioral Risk Factor Surveillance System (BRFSS) state and small area estimates for 2016.

Results

Integrating progressively more variables into prediction models generally reduced mean absolute error (MAE) relative to municipality-level BRFSS small area estimates: asthma (2.24% MAE crude, 1.02% MAE modeled), diabetes (3.13% MAE crude, 3.48% MAE modeled), hypertension (2.60% MAE crude, 1.48% MAE modeled), obesity (4.92% MAE crude, 4.07% MAE modeled), and smoking (5.33% MAE crude, 2.99% MAE modeled). Correlation between modeled estimates and BRFSS estimates for the 13 municipalities in Massachusetts covered by BRFSS’s 500 Cities ranged from 81.9% (obesity) to 96.7% (diabetes).

Conclusions

Small-area estimation using EHR data is feasible and generates estimates comparable to BRFSS state and small-area estimates. Integrating EHR data with survey data can provide timely and accurate disease monitoring tools for areas with sparse data coverage.
Factors influencing uptake of diabetes health screening: a mixed methods study in Asian population
Authors: AshaRani P. V. , Devi Fiona , Wang Peizhi , Abdin Edimansyah , Zhang Yunjue , Roystonn Kumarasan , Jeyagurunathan Anitha , Subramaniam Mythily
Published: August 2022

Background

Health screens are the cornerstones for health promotion and preventive interventions at a community level. This study investigated the barriers and facilitators to the uptake of diabetes health screening in the general population of Singapore.

Methods

In this mixed methods study, participants without diabetes were recruited from the general population. The quantitative phase (n = 2459) included face to face survey of participants selected through disproportionate stratified random sampling. Those who participated in the quantitative survey were then randomly chosen for a one-to-one semi-structured interview (n = 30).

Results

Among the survey respondents, 73.09% (n = 1777) had attended a diabetes health screening in their lifetime whilst 42.36% (n = 1090) and 57.64% (n = 1328, p < 0.0001) attended the health screens regularly (every 12 months) and irregularly, respectively. A significantly higher proportion of older adults (≥ 40 years) attended regular diabetes health screening compared to younger adults (less than 40 years; 55.59% vs 24.90%, p < 0.001). The top 3 reasons for attending regular health screens were to detect diabetes early, to make lifestyle changes in case of a diagnosis and being health conscious. Qualitative interviews identified similar issues and complex nuances that influenced the uptake of regular diabetes health screening. Several personal factors (laziness, self-reliance, psychological factors, etc.), competing priorities, fatalistic beliefs, affordability, misconceptions about the screens, and appointment related factors (inconvenient location, time, etc.) were identified as barriers, while affordable screens, sense of personal responsibility, perception of susceptibility /risk, role of healthcare team (e.g. reminders and prescheduled appointments) and personal factors (e.g. age, family, etc.) were facilitators. Age, household income, ethnicity and educational level were associated with the uptake of regular diabetes health screening.

Conclusion

The uptake of regular diabetes health screening can be improved. Several barriers and enablers to the uptake of diabetes health screening were identified which should be addressed by the policy makers to alleviate misconceptions and create greater awareness of the importance of the programme that will improve participation.
Which countries need COVID-19 vaccines the most? Development of a prioritisation tool
Authors: Jain Vageesh , Atun Rifat , Hansen Paul , Lorgelly Paula
Published: August 2022

Background

The COVID-19 pandemic and associated non-pharmaceutical interventions (NPIs) have affected all countries. With a scarcity of COVID-19 vaccines there has been a need to prioritize populations, but assessing relative needs has been challenging. The COVAX Facility allocates vaccines to cover 20% of each national population, followed by a needs assessment that considers five quantitative metrics alongside a qualitative assessment. The objective of this study was to identify the most important factors for assessing countries’ needs for vaccines, and to weight each, generating a scoring tool for prioritising countries.

Methods

The study was conducted between March and November 2021. The first stage involved an online Delphi survey with a purposive and snowball sample of public health experts, to reach consensus on country-level factors for assessing relative needs for COVID-19 vaccines. The second stage involved a discrete choice experiment (DCE) to determine weights for the most important factors.

Results

Responses were received from 28 experts working across 13 different countries and globally. The most common job titles reported were director and professor, with most based in national public health institutes (n = 9) and universities (n = 8). The Delphi survey found 37 distinct factors related to needs. Nine of the most important factors were included in the DCE. Among these, the most important factor was the ‘proportion of overall population not fully vaccinated’ (with a mean weight of 19.5), followed by ‘proportion of high-risk population not fully vaccinated’ (16.1), ‘health system capacity’ (14.2), ‘capacity to purchase vaccines’ (11.9) and the ‘proportion of the population clinically vulnerable’ (11.3).

Conclusions

Several factors exist, extending beyond those currently used, which may lead to some countries having a greater need for vaccines compared to others. By assessing relative needs, this scoring tool can build on existing methods to further the role of equity in global COVID-19 vaccine allocation.
Comparison of measured and predicted mesiodistal tooth-widths of 13–17 years old Kenyans: a descriptive cross-sectional study to develop a new prediction equation for use in the mixed dentition in a Kenyan population
Authors: Kerre Nduguyu , Ngesa James Lwanga , Ng’ang’a Peter , Kemoli Arthur Musakulu , Bermudez Janella , Seminario Ana Lucia
Published: August 2022

Background

The Tanaka and Johnson equation is commonly used in mixed dentition analysis. However, the analysis is based on  a Caucasian population making clinical decisions challenging when used in different ethnic groups. This study developed a prediction equation based on a Kenyan population.

Design

A descriptive cross-sectional study done in 68 13–17 years old Kenyans of African descent in two boarding secondary schools. Alginate impressions were taken, study models obtained, and mesiodistal tooth-widths measured on upper and lower study models from the first molar to the contralateral first molar. Descriptive statistics, paired t-tests and independent t-tests were conducted and Pearson product-moment correlation coefficients calculated (p < 0.05).

Results

The mean age was 13.78 years (SD ± 0.70), females were 59%. The mesiodistal tooth-widths of the permanent canines and premolars were different between males and females (p ˂ 0.1). The Tanaka and Johnston equation significantly under-estimated the mesiodistal tooth-widths of the permanent canines and premolars (p ˂ 0.05). The addition of lower first permanent molars to the permanent lower incisors provided higher correlation coefficients than the Tanaka Johnston equation.

Conclusions

A new equation that includes the permanent lower incisors and first permanent molars as predictor teeth seems to be more suitable for mixed dentition analysis for this Kenyan population. A larger study is needed to validate these findings.
Cytoreductive prostatectomy improves survival outcomes in patients with oligometastases: a systematic meta-analysis
Authors: Mao Yifeng , Hu Mingqiu , Yang Gaowei , Gao Erke , Xu Wangwang
Published: August 2022

Background

Whether cytoreductive prostatectomy (CRP) should be performed in patients with oligometastatic prostate cancer (OPC) remains controversial. The goal of this systematic meta-analysis was to assess the efficacy of CRP as a treatment for OPC.

Methods

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. Data sources included publications in the PubMed, Embase, the Cochrane Library, EBSCO, and Web of Science (SCI) databases as of May 2022. Eligible articles included prospective studies comparing the efficacy of CRP to a lack of CRP in patients with OPC.

Results

In total, 10 publications incorporating 888 patients were analyzed. Tumor-reducing prostatectomy was found to have no significant effect on long-term or short-term OS [OR = 2.26, 95% CI (0.97, 5.28), P = 0.06] and [OR = 1.73, 95% CI (0.83, 3.58), P = 0.14], but it significantly improved patient long-term or short-term CSS [OR = 1.77, 95% CI (1.01, 310), P = 0.04] and [OR = 2.71, 95% CI (1.72, 4.29), P < 0.0001] and PFS [OR = 1.93, 95% CI (1.25, 2.97), P = 0.003].

Conclusion

These results suggest that cytoreductive prostatectomy can confer survival benefits to OPC patients.

Trial registration

INPLASY protocol 202260017 https://doi.org/10.37766/inplasy2022.6.0017.
Callispheres® drug-eluting beads transarterial chemoembolization might be an efficient and safety down-staging therapy in unresectable liver cancer patients
Authors: Peng Ning , Mao Linfeng , Tao Yiwen , Xiao Kaiyin , Yuan Guandou , He Songqing
Published: August 2022

Purpose

The purpose was to explore the effect of drug-eluting beads transarterial chemoembolization (DEB-TACE) on down-staging in unresectable liver cancer patients.

Methods

A total of 180 patients with PHC treated by TACE were retrospectively analyzed. These included 80 cases in the DEB-TACE group and 100 cases in the cTACE group. Of these, 56 had complete clinical data (DEB-TACE: 24, cTACE: 32), and 23 patients received hepatectomy after TACE as a down-staging therapy (DEB-TACE: 15, cTACE: 8). Data (including clinical characteristics, clinical efficacy, tumor response, tumor diameters, residual liver volume, and liver function indexes before and after TACE, RFS, OS, and complications were collected and compared. Treatment response was evaluated at 1 month after TACE. Tumor diameter was evaluated by abdominal computed tomography scan. The residual liver volume was evaluated by IQQA liver system, and relapse-free survival (RFS) and overall survival (OS) were calculated by Kaplan–Meier curves.

Results

The conversion rate in DEB-TACE group was higher than cTACE group (18.8% vs 8%, p = 0.032). In DEB-TACE group, 17 patients achieved objective response rate (ORR) which was higher than cTACE group (70.8% vs 34.4%, p = 0.007). The tumor necrosis rate was higher in DEB-TACE group, but there was no significant difference between the two groups (p = 0.053). Tumor diameter was decreased after TACE compared to before TACE (DEB-TACE: 9.4 ± 3.3 vs. 5.4 ± 3.5 cm, p = 0.003; cTACE: 9.7 ± 2.6 vs. 6.9 ± 2.2, p = 0.036). As to residual liver volume, it was increased after TACE compared to before TACE (1066.2 cm3 vs. 1180.3 cm3, p = 0.007) in DEB-TACE group, while there was no significant difference in cTACE group (1046.4 cm3 vs. 1170 cm3, p = 0.339) compared by paired-sample t-test, but there was no significant difference before and after TACE when compared by unpaired-sample t-test (p > 0.05). After TACE at 1 month, the AFP level in the DEB-TACE group was significantly lower than that in the cTACE group (p = 0.003). For survival, the median RFS was 26.0 months in DEB-TACE group and 15 months in cTACE group; there was significant difference between the two groups (p = 0.0465). As to OS, the median OS in DEB-TACE group was higher than that in cTACE group, but there was no significant difference between the two groups (p = 0.165). For safety profiles, in terms of liver function and adverse events, there was no significant difference between the two groups.

Conclusion

Compared with cTACE, DEB-TACE might be a more efficient and safety down-staging treatment in unresectable liver cancer patients.
Competing public narratives in nutrition policy: insights into the ideational barriers of public support for regulatory nutrition measures
Authors: Cullerton Katherine , Patay Dori , Waller Michael , Adsett Eloise , Lee Amanda
Published: August 2022

Background

Enacting evidence-based public health policy can be challenging. One factor contributing to this challenge is a lack of public support for specific policies, which may stem from limited interest or conviction by policy arguments. This can happen when messaging strategies regarding policy do not resonate with the target group and/or policy narratives compete in public discourse. To understand how policy messaging can better resonate with a target audience, we examined the frames and narratives used by the Australian public when discussing nutrition policies.

Methods

We conducted 76 street intercept interviews in urban and regional settings in Queensland, Australia. Quantitative data were analysed using mean agreement scores and t-tests, and the qualitative data were analysed using an adapted qualitative narrative policy framework (QNPF). The QNPF is used to illustrate how competing narratives vary in the way they define different elements. These elements often include setting, characters, plot, policy solution and belief systems.

Results

Level of support for all nutrition policies was generally moderate to high, although nutrition policies perceived to be most intrusive to personal freedoms were the least popular among the public. The value of fairness was consistently invoked when participants discussed their support for or opposition to policy. Using the QNPF, two distinct settings were evident in the narratives: concern for the community or concern for self. Villains were identified as either “other individuals, in particular parents” or “Big Food”. Victims were identified as “children” or “the food industry, in particular farmers”. Frequently used plots focused on individuals making poor choices because they were uneducated, versus Big Food being powerful and controlling people and the government.

Conclusions

The study examined the frames and narratives used by the Australian public when discussing nutrition policies. By examining these frames and narratives, we gained insight into multiple strategies which may increase public support for certain nutrition policies in Australia.
Interrelationships and determinants of aging biomarkers in cord blood
Authors: Reimann Brigitte , Martens Dries S. , Wang Congrong , Ghantous Akram , Herceg Zdenko , Plusquin Michelle , Nawrot Tim S.
Published: August 2022

Background

Increasing evidence supports the concept of prenatal programming as an early factor in the aging process. DNA methylation age (DNAm age), global genome-wide DNA methylation (global methylation), telomere length (TL), and mitochondrial DNA content (mtDNA content) have independently been shown to be markers of aging, but their interrelationship and determinants at birth remain uncertain.

Methods

We assessed the inter-correlation between the aging biomarkers DNAm age, global methylation, TL and mtDNA content using Pearson's correlation in 190 cord blood samples of the ENVIRONAGE birth cohort. TL and mtDNA content was measured via qPCR, while the DNA methylome was determined using the human 450K methylation Illumina microarray. Subsequently, DNAm age was calculated according to Horvath's epigenetic clock, and mean global, promoter, gene-body, and intergenic DNA methylation were determined. Path analysis, a form of structural equation modeling, was performed to disentangle the complex causal relationships among the aging biomarkers and their potential determinants.

Results

DNAm age was inversely correlated with global methylation (r = -0.64, p < 0.001) and mtDNA content (r = − 0.16, p = 0.027). Cord blood TL was correlated with mtDNA content (r = 0.26, p < 0.001) but not with global methylation or DNAm age. Path analysis showed the strongest effect for global methylation on DNAm age with a decrease of 0.64 standard deviations (SD) in DNAm age for each SD (0.01%) increase in global methylation (p < 0.001). Among the applied covariates, newborn sex and season of delivery were the strongest determinants of aging biomarkers.

Conclusions

We provide insight into molecular aging signatures at the start of life, including their interrelations and determinants, showing that cord blood DNAm age is inversely associated with global methylation and mtDNA content but not with newborn telomere length. Our findings demonstrate that cord blood TL and DNAm age relate to different pathways/mechanisms of biological aging and can be influenced by environmental factors already at the start of life. These findings are relevant for understanding fetal programming and for the early prevention of noncommunicable diseases.

Graphical Abstract
Fused ultrasound and electromyography-driven neuromuscular model to improve plantarflexion moment prediction across walking speeds
Authors: Zhang Qiang , Fragnito Natalie , Franz Jason R. , Sharma Nitin
Published: August 2022

Background

Improving the prediction ability of a human-machine interface (HMI) is critical to accomplish a bio-inspired or model-based control strategy for rehabilitation interventions, which are of increased interest to assist limb function post neurological injuries. A fundamental role of the HMI is to accurately predict human intent by mapping signals from a mechanical sensor or surface electromyography (sEMG) sensor. These sensors are limited to measuring the resulting limb force or movement or the neural signal evoking the force. As the intermediate mapping in the HMI also depends on muscle contractility, a motivation exists to include architectural features of the muscle as surrogates of dynamic muscle movement, thus further improving the HMI’s prediction accuracy.

Objective

The purpose of this study is to investigate a non-invasive sEMG and ultrasound (US) imaging-driven Hill-type neuromuscular model (HNM) for net ankle joint plantarflexion moment prediction. We hypothesize that the fusion of signals from sEMG and US imaging results in a more accurate net plantarflexion moment prediction than sole sEMG or US imaging.

Methods

Ten young non-disabled participants walked on a treadmill at speeds of 0.50, 0.75, 1.00, 1.25, and 1.50 m/s. The proposed HNM consists of two muscle-tendon units. The muscle activation for each unit was calculated as a weighted summation of the normalized sEMG signal and normalized muscle thickness signal from US imaging. The HNM calibration was performed under both single-speed mode and inter-speed mode, and then the calibrated HNM was validated across all walking speeds.

Results

On average, the normalized moment prediction root mean square error was reduced by 14.58 % ($$p=0.012$$

p
=
0.012

) and 36.79 % ($$p<0.001$$

p
<
0.001

) with the proposed HNM when compared to sEMG-driven and US imaging-driven HNMs, respectively. Also, the calibrated models with data from the inter-speed mode were more robust than those from single-speed modes for the moment prediction.

Conclusions

The proposed sEMG-US imaging-driven HNM can significantly improve the net plantarflexion moment prediction accuracy across multiple walking speeds. The findings imply that the proposed HNM can be potentially used in bio-inspired control strategies for rehabilitative devices due to its superior prediction.
Motorless cadence control of standard and low duty cycle-patterned neural stimulation intensity extends muscle-driven cycling output after paralysis
Authors: Gelenitis Kristen , Foglyano Kevin , Lombardo Lisa , McDaniel John , Triolo Ronald
Published: August 2022

Background

Stimulation-driven exercise is often limited by rapid fatigue of the activated muscles. Selective neural stimulation patterns that decrease activated fiber overlap and/or duty cycle improve cycling exercise duration and intensity. However, unequal outputs from independently activated fiber populations may cause large discrepancies in power production and crank angle velocity among pedal revolutions. Enforcing a constant cadence through feedback control of stimulus levels may address this issue and further improve endurance by targeting a submaximal but higher than steady-state exercise intensity.

Methods

Seven participants with paralysis cycled using standard cadence-controlled stimulation (S-Cont). Four of those participants also cycled with a low duty cycle (carousel) cadence-controlled stimulation scheme (C-Cont). S-Cont and C-Cont patterns were compared with conventional maximal stimulation (S-Max). Outcome measures include total work (W), end power (Pend), power fluctuation (PFI), charge accumulation (Q) and efficiency (η). Physiological measurements of muscle oxygenation (SmO2) and heart rate were also collected with select participants.

Results

At least one cadence-controlled stimulation pattern (S-Cont or C-Cont) improved Pend over S-Max in all participants and increased W in three participants. Both controlled patterns increased Q and η and reduced PFI compared with S-Max and prior open-loop studies. S-Cont stimulation also delayed declines in SmO2 and increased heart rate in one participant compared with S-Max.

Conclusions

Cadence-controlled selective stimulation improves cycling endurance and increases efficiency over conventional stimulation by incorporating fiber groups only as needed to maintain a desired exercise intensity. Closed-loop carousel stimulation also successfully reduces power fluctuations relative to previous open-loop efforts, which will enable neuroprosthesis recipients to better take advantage of duty cycle reducing patterns.
The potential involvement of inhaled iron (Fe) in the neurotoxic effects of ultrafine particulate matter air pollution exposure on brain development in mice
Authors: Sobolewski Marissa , Conrad Katherine , Marvin Elena , Eckard Matthew , Goeke Calla M. , Merrill Alyssa K. , Welle Kevin , Jackson Brian P. , Gelein Robert , Chalupa David , Oberdörster Günter , Cory-Slechta Deborah A.
Published: August 2022

Background

Air pollution has been associated with neurodevelopmental disorders in epidemiological studies. In our studies in mice, developmental exposures to ambient ultrafine particulate (UFP) matter either postnatally or gestationally results in neurotoxic consequences that include brain metal dyshomeostasis, including significant increases in brain Fe. Since Fe is redox active and neurotoxic to brain in excess, this study examined the extent to which postnatal Fe inhalation exposure, might contribute to the observed neurotoxicity of UFPs. Mice were exposed to 1 µg/m3 Fe oxide nanoparticles alone, or in conjunction with sulfur dioxide (Fe (1 µg/m3) + SO2 (SO2 at 1.31 mg/m3, 500 ppb) from postnatal days 4–7 and 10–13 for 4 h/day.

Results

Overarching results included the observations that Fe + SO2 produced greater neurotoxicity than did Fe alone, that females appeared to show greater vulnerability to these exposures than did males, and that profiles of effects differed by sex. Consistent with metal dyshomeostasis, both Fe only and Fe + SO2 exposures altered correlations of Fe and of sulfur (S) with other metals in a sex and tissue-specific manner. Specifically, altered metal levels in lung, but particularly in frontal cortex were found, with reductions produced by Fe in females, but increases produced by Fe + SO2 in males. At PND14, marked changes in brain frontal cortex and striatal neurotransmitter systems were observed, particularly in response to combined Fe + SO2 as compared to Fe only, in glutamatergic and dopaminergic functions that were of opposite directions by sex. Changes in markers of trans-sulfuration in frontal cortex likewise differed in females as compared to males. Residual neurotransmitter changes were limited at PND60. Increases in serum glutathione and Il-1a were female-specific effects of combined Fe + SO2.

Conclusions

Collectively, these findings suggest a role for the Fe contamination in air pollution in the observed neurotoxicity of ambient UFPs and that such involvement may be different by chemical mixture. Translation of such results to humans requires verification, and, if found, would suggest a need for regulation of Fe in air for public health protection.
Effects of lactation room quality on working mothers’ feelings and thoughts related to breastfeeding and work: a randomized controlled trial and a field experiment
Authors: van Dellen Sjoukje A. , Wisse Barbara , Mobach Mark P.
Published: August 2022

Background

The challenging combination of breastfeeding and work is one of the main reasons for early breastfeeding cessation. Although the availability of a lactation room (defined as a private space designated for milk expression or breastfeeding) is important in enabling the combination of breastfeeding and work, little is known about the effects of lactation room quality on mothers’ feelings and thoughts related to breastfeeding and work. We hypothesized that a high-quality lactation room (designed using the Theory of Supportive Design) would cause mothers to experience less stress, have more positive thoughts about milk expression at work, perceive more organizational support, and report more subjective well-being, than a low-quality lactation room.

Methods

In an online randomized controlled trial (Study 1), Dutch mothers (N = 267) were shown either a high-quality or a low-quality lactation room (using pictures and descriptions for the manipulation) and were then asked about their feelings and thoughts. In a subsequent field experiment (Study 2) we modified the lactations rooms in a large organization in Groningen, the Netherlands, to manipulate lactation room quality, and asked mothers (N = 61) who used either a high-quality or low-quality lactation room to fill out surveys to assess the dependent variables.

Results

The online study showed that mothers exposed to the high-quality lactation room anticipated less stress, more positive cognitions about milk expression at work, more perceived organizational support, and more subjective well-being than mothers exposed to the low-quality lactation room (p <  0.05). Moreover, the effect of lactation room quality on perceived organizational support was especially pronounced for mothers who were higher in environmental sensitivity. The field experiment showed that use of the high-quality room led to less reported stress than use of the low-quality room (p <  0.05). We also found that mothers who were higher in environmental sensitivity perceived more control over milk expression at work and experienced more subjective well-being in the high-quality condition than in the low-quality condition (p <  0.05).

Conclusion

The current studies show that not only the availability, but also the quality of lactation rooms is important in facilitating the combination of breastfeeding and work.
Vitamin B12 in Leber hereditary optic neuropathy mutation carriers: a prospective cohort study
Authors: Zibold Julia , von Livonius Bettina , Kolarova Hana , Rudolph Günter , Priglinger Claudia S. , Klopstock Thomas , Catarino Claudia B.
Published: August 2022

Background

Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12 deficiency in a large cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral center.

Methods

From the Munich LHON prospective cohort study, participants included all LHON patients and asymptomatic LHON mutation carriers, who were recruited between February 2014 and March 2020 and consented to participate. Neurological, general, and ophthalmological examinations were regularly performed, as were laboratory tests. Vitamin B12 deficiency was diagnosed if serum vitamin B12 was below 201 pg/mL, or if 201–339 pg/mL plus low serum holotranscobalamin or elevated serum methylmalonic acid or elevated total plasma homocysteine.

Results

We analyzed 244 subjects, including 147 symptomatic LHON patients (74% males) and 97 asymptomatic mutation carriers (31% males). Median age at study baseline was 34 years (range 5–82 years). The prevalence of vitamin B12 deficiency was higher for LHON mutation carriers than for the general population in all age categories. This was statistically significant for the LHON mutation carriers under 65 years (21% vs. 5–7%, p = 0.002). While vitamin B12 deficiency prevalence was not statistically different between LHON patients and asymptomatic mutation carriers, its clinical correlates, e.g., macrocytosis and polyneuropathy, were more frequent in the subgroup of LHON patients. Excessive alcohol consumption was a significant predictor of vitamin B12 deficiency (p < 0.05).

Conclusions

The high prevalence of vitamin B12 deficiency in LHON mutation carriers, both asymptomatic mutation carriers and LHON patients, highlights the need for regular vitamin B12 screening in this population, in order to ensure early treatment, aiming for better outcomes. Our study is not conclusive regarding vitamin B12 deficiency as determinant for disease conversion in LHON, and further research is warranted to disentangle the role of vitamin B12 in the pathophysiology and prognosis of LHON.
Single-cell diploid Hi-C reveals the role of spatial aggregations in complex rearrangements and KMT2A fusions in leukemia
Authors: Xing Zhihao , Mai Huirong , Liu Xiaorong , Fu Xiaoying , Zhang Xingliang , Xie Lichun , Chen Yunsheng , Shlien Adam , Wen Feiqiu
Published: August 2022

Background

Simple translocations and complex rearrangements are formed through illegitimate ligations of double-strand breaks of fusion partners and lead to generation of oncogenic fusion genes that affect cellular function. The contact first hypothesis states that fusion partners tend to colocalize prior to fusion in normal cells. Here we test this hypothesis at the single-cell level and explore the underlying mechanism.

Results

By analyzing published single-cell diploid Hi-C datasets, we find partner genes fused in leukemia exhibit smaller spatial distances than those fused in solid tumor and control gene pairs. Intriguingly, multiple partners tend to colocalize with KMT2A in the same cell. 3D genome architecture has little association with lineage decision of KMT2A fusion types in leukemia. Besides simple translocations, complex rearrangement-related KMT2A fusion genes (CRGs) also show closer proximity and belong to a genome-wide mutual proximity network. We find CRGs are co-expressed, co-localized, and enriched in the targets of the transcriptional factor RUNX1, suggesting they may be involved in RUNX1-mediated transcription factories. Knockdown of RUNX1 leads to significantly fewer contacts among CRGs. We also find CRGs are enriched in active transcriptional regions and loop anchors, and exhibit high levels of TOP2-mediated DNA breakages. Inhibition of transcription leads to reduced DNA breakages of CRGs.

Conclusions

Our results demonstrate KMT2A partners and CRGs may form dynamic and multipartite spatial clusters in individual cells that may be involved in RUNX1-mediated transcription factories, wherein massive DNA damages and illegitimate ligations of genes may occur, leading to complex rearrangements and KMT2A fusions in leukemia.
Successes and lessons learned in database development for national multi-site cancer care delivery research trials: the Alliance for Clinical Trials in Oncology experience
Authors: Zahrieh David , Hillman Shauna L. , Tan Angelina D. , Frank Jennifer L. , Dockter Travis , Meyers Bobbi Jo , Cherevko Cassie L. , Peil Elizabeth S. , McCue Shaylene , Kour Oudom , Gunn Heather J. , Neuman Heather B. , Chang George J. , Paskett Electra D. , Mandrekar Sumithra J. , Dueck Amylou C.
Published: August 2022

Introduction

Alliance for Clinical Trials in Oncology (Alliance) coordinated trials utilize Medidata Rave® (Rave) as the primary clinical data capture system. A growing number of innovative and complex cancer care delivery research (CCDR) trials are being conducted within the Alliance with the aims of studying and improving cancer-related care. Because these trials encompass patients, providers, practices, and their interactions, a defining characteristic of CCDR trials is multilevel data collection in pragmatic settings. Consequently, CCDR trials necessitated innovative strategies for database development, centralized data management, and data monitoring in the presence of these real-world multilevel relationships. Having real trial experience in working with community and academic centers, and having recently implemented five CCDR trials in Rave, we are committed to sharing our strategies and lessons learned in implementing such pragmatic trials in oncology.

Methods

Five Alliance CCDR trials are used to describe our approach to analyzing the database development needs and the novel strategies applied to overcome the unanticipated challenges we encountered. The strategies applied are organized into 3 categories: multilevel (clinic, clinic stakeholder, patient) enrollment, multilevel quantitative and qualitative data capture, including nontraditional data capture mechanisms being applied, and multilevel data monitoring.

Results

A notable lesson learned in each category was (1) to seek long-term solutions when developing the functionality to push patient and non-patient enrollments to their respective Rave study database that affords flexibility if new participant types are later added; (2) to be open to different data collection modalities, particularly if such modalities remove barriers to participation, recognizing that additional resources are needed to develop the infrastructure to exchange data between that modality and Rave; and (3) to facilitate multilevel data monitoring, orient site coordinators to the their trial’s multiple study databases, each corresponding to a level in the hierarchy, and remind them to establish the link between patient and non-patient participants in the site-facing NCI web-based enrollment system.

Conclusion

Although the challenges due to multilevel data collection in pragmatic settings were surmountable, our shared experience can inform and foster collaborations to collectively build on our past successes and improve on our past failures to address the gaps.
Optimising recruitment in clinical trials for progressive multiple sclerosis: observational analysis from the MS-SMART and MS-STAT2 randomised controlled trials
Authors: Williams Thomas , Alexander Sarah , Blackstone James , De Angelis Floriana , John Nevin , Doshi Anisha , Beveridge Judy , Braisher Marie , Gray Emma , Chataway Jeremy ,   on behalf of the MS-SMART and MS-STAT2 Investigators
Published: August 2022

Background

Slower than planned recruitment is a major factor contributing to the delay or failure of randomised controlled trials to report on time. There is a limited evidence base regarding the optimisation of recruitment strategies. Here we performed an observational review of our experience in recruitment for two large randomised controlled trials for people with secondary progressive multiple sclerosis. We aimed to explicitly determine those factors which can facilitate trial recruitment in progressive neurodegenerative disease.

Methods

Recruitment data from the sequential MS-SMART [NCT01910259] and MS-STAT2 [NCT03387670] UK randomised controlled trials was reviewed from the largest recruiting site, University College London (UCL). The trial population was similar which allowed comparison over the two recruitment periods of 2015–2016 and 2018–2021. This included sources of referral, progress through stages of recruitment, reasons for participant ineligibility and the impact of publicity events upon recruitment.

Results

In MS-SMART, 18% of patients contacted were enrolled, compared to 27% for MS-STAT2. Online registration of interest portals provided the greatest number of referrals (76% in MS-SMART, and 51% in MS-STAT2), with publicity in national media outlets producing a demonstrable increase in the number of potential participants. The introduction of an online self-screening questionnaire for MS-STAT2 resulted in 67% of potential participants (3080 of 4605) automatically determining their own ineligibility. In both studies, however, around 60% of those directly telephoned to discuss the study were not eligible, with difficulties related to travel to trial visits, or excluded medication, being the most common issues. Eighty-four percent of those deemed potentially eligible following telephone calls were enrolled in the MS-STAT2 study, compared to only 55% for MS-SMART.

Conclusions

Through a detailed review of recruiting participants at the largest centre into two large randomised controlled trials with similar entry criteria, we have identified a number of approaches that may improve recruitment efficiency. We highlight here the importance of mandatory online self-screening questionnaires, a coordinated publicity campaign, and simple interventions such as eligibility checklists and appointment reminders. Recruitment approaches should be further assessed through a studies within a trial (SWAT) design.

Trial registration

MS-SMART: NCT01910259; registered July 2013 and MS-STAT2: NCT03387670; registered Jan 2018
Enhanced rare disease mapping for phenome-wide genetic association in the UK Biobank
Authors: Patrick Matthew T. , Bardhi Redina , Zhou Wei , Elder James T. , Gudjonsson Johann E. , Tsoi Lam C.
Published: August 2022

Background

Rare diseases collectively affect up to 10% of the population, but often lack effective treatment, and typically little is known about their pathophysiology. Major challenges include suboptimal phenotype mapping and limited statistical power. Population biobanks, such as the UK Biobank, recruit many individuals who can be affected by rare diseases; however, investigation into their utility for rare disease research remains limited. We hypothesized the UK Biobank can be used as a unique population assay for rare diseases in the general population.

Methods

We constructed a consensus mapping between ICD-10 codes and ORPHA codes for rare diseases, then identified individuals with each rare condition in the UK Biobank, and investigated their age at recruitment, sex bias, and comorbidity distributions. Using exome sequencing data from 167,246 individuals of European ancestry, we performed genetic association controlling for case/control imbalance (SAIGE) to identify potential rare pathogenic variants for each disease.

Results

Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p = 1.24 × 10−13) and a novel CALR loss of function variant for essential thrombocythemia (p = 1.59 × 10−13). We constructed an interactive resource highlighting demographic information (http://www-personal.umich.edu/~mattpat/rareDiseases.html) and demonstrate transferability by applying our mapping to a medical claims database.

Conclusions

Enhanced disease mapping and increased power from population biobanks can elucidate the demographics and genetic associations for rare diseases.
The risk of newly diagnosed cancer in patients with rheumatoid arthritis by TNF inhibitor use: a nationwide cohort study
Authors: Choi Boyoon , Park Hyun Jin , Song Yun-Kyoung , Oh Yoon-Jeong , Kim In-Wha , Oh Jung Mi
Published: August 2022

Background

Tumor necrosis factor (TNF) inhibitors use in patients with rheumatoid arthritis (RA) has raised safety concerns about cancer risk, but study results remain controversial. This largest nationwide study to date compared cancer risk in TNF inhibitor users to non-biologic disease-modifying anti-rheumatic drug (nbDMARD) users in Korean patients with RA.

Methods

Data on all the eligible patients diagnosed with RA between 2005 and 2016 were retrieved from the Korean National Health Information Database. The one-to-one matched patients consisted of the matched cohort. The risks for developing all-type and site-specific cancers were estimated using incidence and incidence rate (IR) per 1000 person-years. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using a Cox regression model.

Results

Of the 22,851 patients in the before matching cohort, 4592 patients were included in the matched cohort. Treatment with TNF inhibitors was consistently associated with a lower risk of cancer than in the nbDMARD cohort (IR per 1000 person-years, 6.5 vs. 15.6; adjusted HR, 0.379; 95% CI, 0.255–0.563). The adjusted HR (95% CI) was significantly lower in the TNF inhibitor cohort than the nbDMARD cohort for gastrointestinal cancer (0.432; 0.235–0.797), breast cancer (0.146; 0.045–0.474), and genitourinary cancer (0.220; 0.059–0.820).

Conclusions

The use of TNF inhibitors was not associated with an increased risk of cancer development, and rather associated with a lower cancer incidence in Korean patients with RA. Cautious interpretation is needed not to oversimplify the study results as cancer-protective effects of TNF inhibitors. A further study linking claims and clinical data is needed to confirm our results.
Climate envelope analyses suggests significant rearrangements in the distribution ranges of Central European tree species
Authors: Illés Gábor , Móricz Norbert
Published: August 2022

Key message

Climate envelope analysis of nine tree species shows that Fagus sylvatica L. and Picea abies H. Karst could lose 58% and 40% of their current distribution range. Quercus pubescens Willd and Quercus cerris L. may win areas equal with 47% and 43% of their current ranges. The ratio of poorly predictable areas increases by 105% in southern and south-eastern Europe.

Context

Climate change requires adaptive forest management implementations. To achieve climate neutrality, we have to maintain and expand forest areas. Impact assessments have great importance.

Aims

The study estimates the potential climate envelopes of nine European tree species for a past period (1961–1990) and for three future periods (2011–2040, 2041–2070, 2071–2100) under two emission scenarios (RCP4.5 and RCP8.5) based on the current species distribution.

Methods

Climate envelopes were estimated simultaneously using the random forest method. Multi-resolution segmentation was used to determine the climatic characteristics of each species and their combinations. Models were limited to the geographical area within which the climatic conditions correspond to the climatic range of the training areas.

Results

Results showed remarkable changes in the extent of geographic areas of all the investigated species’ climate envelopes. Many of the tree species of Central Europe could lose significant portions of their distribution range. Adhering to the shift in climate, these tree species shift further north as well as towards higher altitudes.

Conclusion

European forests face remarkable changes, and the results support climate envelope modelling as an important tool that provides guidelines for climate adaptation to identify threatened areas or to select source and destination areas for reproductive material.