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Abstract Background During the day-night cycle, gravity and applied stress to the body mass and spine causes a decrease in body height, which is restored overnight. This diurnal spine length variation has not yet been quantified during radiotherapy. Therefore, we aimed to quantify diurnal spine length variation on cone beam CTs (CBCTs) of pediatric patients (

Abstract Background Dental anxiety is a global problem in the realm of pediatric dentistry. The use of procedural sedation is recommended to avoid substandard or unsafe dental treatment in preschoolers. This study aimed to compare the effect sedation with Dexmedetomidine with or without Midazolam in terms of sedation level, analgesic effect and ease of treatment completion in preschool children. Methods A triple blind randomized controlled clinical trial comprised 72 healthy uncooperative children, 4–6 years old, were randomly allocated into three groups of 24 patients each: Group I patients were sedated with nebulized 5 μg/kg Dexmedetomidine (DEX), Group II with nebulized 3 μg/kg DEX followed by nebulized 0.3 mg/kg Midazolam (MID), and Group III with nebulized 0.5 mg/kg MID. Along the session, the three regimens were assessed and compared during the sedation level (children responsiveness) using the Modified Observer’s Assessment of Alertness/Sedation Scale, the analgesic effect using the Face, Leg, Activity, Cry, Consolability scale and ease of treatment completion using a separate 5-point scale. Vital signs were recorded before and during sedation, until full recovery. Results A significant difference was detected regarding children responsiveness during operative procedure in favour of DEX in comparison to MID and DEX/MID groups (P = 0.045). Within the DEX group, a significant difference was recorded regarding children responsiveness at optimum sedation and during the operative procedure (P = 0.04). Although, the analgesic effects of sedative drugs showed no statistically significant difference among the study groups (P = 0.20), the ease of treatment completion was statistically higher in the DEX than MID and DEX/MID groups (P = 0.03). Conclusion Dexmedetomidine provides a moderate level of sedation, that allowed better patient cooperation, and easy completion of performed dental procedures.

Abstract Background Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA). Methods We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored. Results We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells. Conclusions BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity.

ABSTRACT Objectives: To evaluate the impact of COVID-19 pandemics on clinical and surgical practice, educational activities, health and lifestyle behavior of Brazilian urology residents after 1 year of socio-economic restrictions. Materials and Methods: An electronic survey was e-mailed to all postgraduate (PG) students registered by the Brazilian Society of Urology. The survey included an assessment of socio-demographic, clinical practice, educational, health-related and behavior parameters. We also evaluated which subareas of urology were predominantly affected. A similar survey was adapted and sent to the directors of all urology residency programs. Results: COVID-19 pandemic has severely impacted the clinical, surgical, and educational activities of urology residents in Brazil. Urology residents reported >50% decrease in multiple surgical modalities. We highlight kidney transplantation surgeries (66.2%), minor surgeries (62.3%), endoscopic surgeries (42.6%) and reconstructive surgeries (38.8%). This could represent a critical skills gap that residents may face beyond the COVID-19 pandemic. Furthermore, PG students faced stressful situations that caused worsening of mental and physical health, such as getting redirected to assistance of COVID-19 patients (66.9%), and high rate of infection by SARS-CoV-2 (58.2%). Conclusions: The COVID-19 pandemic has severely impacted the clinical, surgical, and educational activities of urology residents in Brazil. This could represent a critical skills gap that residents may face beyond the COVID-19 pandemic. PG students faced stressful situations that caused worsening of mental and physical health such as redirection to assistance of COVID-19 patients, concern about their own contamination and of family members.

Abstract Materials with field-tunable polarization are of broad interest to condensed matter sciences and solid-state device technologies. Here, using hydrogen (H) donor doping, we modify the room temperature metallic phase of a perovskite nickelate NdNiO3 into an insulating phase with both metastable dipolar polarization and space-charge polarization. We then demonstrate transient negative differential capacitance in thin film capacitors. The space-charge polarization caused by long-range movement and trapping of protons dominates when the electric field exceeds the threshold value. First-principles calculations suggest the polarization originates from the polar structure created by H doping. We find that polarization decays within ~1 second which is an interesting temporal regime for neuromorphic computing hardware design, and we implement the transient characteristics in a neural network to demonstrate unsupervised learning. These discoveries open new avenues for designing ferroelectric materials and electrets using light-ion doping.

Abstract Background Pulpotomy procedures aiming to preserve and regenerate the dentin-pulp complex have recently increased exponentially due to developments in the field of biomaterials and tissue engineering in primary and permanent teeth. Although the number of studies in this domain has increased, there is still scarcity of evidence in the current literature. Objectives (1) Report the methods of outcome assessment of pulpotomy clinical trials in both primary and permanent teeth; (2) Identify the various bioactive agents and biodegradable scaffolds used in pulpotomy clinical trials in both primary and permanent teeth. Materials and methods A scoping review of the literature was performed, including a search of primary studies on PubMed, Scopus, Web of Science, ProQuest and Clinicaltrials.gov. A search for controlled trials or randomized controlled trials published between 2012 and 2023 involving primary or permanent teeth receiving partial or full pulpotomy procedures using bioactive/regenerative capping materials was performed. Results 127 studies out of 1038 articles fulfilled all the inclusion criteria and were included in the current scoping review. More than 90% of the studies assessed clinical and radiographic outcomes. Histological, microbiological, or inflammatory outcomes were measured in only 9.4% of all included studies. Majority of the studies (67.7%) involved primary teeth. 119 studies used non-degradable bioactive cements, while biodegradable scaffolds were used by 32 studies, natural derivates and plant extracts studies were used in only 7 studies. Between 2012 (4 studies) and 2023 (11 studies), there was a general increase in the number of articles published. India, Egypt, Turkey, and Iran were found to have the highest total number of articles published (28, 28,16 and 10 respectively). Conclusions Pulpotomy studies in both primary and permanent teeth relied mainly on subjective clinical and radiographic outcome assessment methods and seldom analyzed pulpal inflammatory status objectively. The use of biodegradable scaffolds for pulpotomy treatments has been increasing with an apparent global distribution of most of these studies in low- to middle-income countries. However, the development of a set of predictable outcome measures as well as long-term evidence from well conducted clinical trials for novel pulpotomy dressing materials are still required.

Abstract Objective The aim of this study was to evaluate and compare reliability, costs, and radiation dose of dual-energy X-ray absorptiometry (DXA) to MRI and CT in measuring muscle mass for the diagnosis of sarcopenia. Methods Thirty-four consecutive DXA scans performed in surgically menopausal women from November 2019 until March 2020 were analyzed by two observers. Observers analyzed muscle mass of the lower limbs in every scan twice. Reliability was assessed by calculating inter- and intra-observer variability. Reliability from CT and MRI as well as radiation dose from CT and DXA were collected from literature. Costs for each type of scan were calculated according to the guidelines for economic evaluation of the Dutch National Health Care Institute. Results The 34 participants had a median age of 58 years (IQR 53–65) and a median body mass index of 24.6 (IQR 21.7–29.7). Inter-observer variability had an intraclass correlation coefficient (ICC) of 0.997 (95% CI 0.994–0.998) with a relative variability of 0.037 ± 0.022%. Regarding intra-observer variability, observer 1 had an ICC of 0.998 (95% CI 0.996–0.999) with a relative variability of 0.019 ± 0.016% and observer 2 had an ICC of 0.997 (95% CI 0.993–0.998) with a relative variability of 0.016 ± 0.011%. DXA costs were €62, CT €77, and MRI €195. The estimated radiation dose of CT was 2.5–3.0 mSv, for DXA this was 2–4 µSv. Conclusions DXA has lower costs and a lower radiation dose, with low inter- and intra-observer variability, compared to CT and MRI for assessing lower limb muscle mass. Trial registration Netherlands Trial Register; NL8068. Critical relevance statement DXA is a good alternative for CT and MRI in assessing lower limb muscle mass, with lower costs and lower radiation dose, while inter-observer and intra-observer variability are low. Key points • Screening for sarcopenia should be optimized as the population ages. • DXA outperformed CT and MRI in the measured metrics. • DXA validity should be further evaluated as an alternative to CT and MRI for sarcopenia evaluation. Graphical Abstract

Background and objective: The adjustable transobturator male system (ATOMS) is an established treatment for patients with urinary incontinence after prostate surgery. Our objective was to evaluate the efficacy and the complication burdens associated with ATOMS with a focus on exploring the potential impact on previous radiotherapy (RT). Methods: We performed a retrospective analysis for consecutive patients who underwent ATOMS implantation procedure at a tertiary center over an 11-yr study period. Outcomes of interest were dryness at 3-mo follow up, postoperative complications (≤30 d), and late treatment failures (>30 d). Key findings and limitations: A total of 118 patients underwent ATOMS surgery performed by five different surgeons. Median follow-up was 67 mo (interquartile range 41–95). The mean 24-h pad count after surgery was 1.1 (range 0–8) and the mean reduction in pad weight was 179 g (range 0–1080). There was no significant difference in the reduction in pad use between groups with and without RT (−1.7 vs −2.4; p = 0.13). Multivariable analysis revealed that RT, degree of incontinence, and age were not risk factors for reoperation. Conclusions and clinical implications: ATOMS implantation is feasible in patients who have undergone prostate RT and patients with severe stress urinary incontinence after prostate surgery. We found that RT was not a risk factor for reoperation and there was no significant difference in pad weight reduction by RT status. This study offers new insight into potential incontinence surgery for male patients with stress urinary incontinence and previous RT. Patient summary: We assessed outcomes for patients who had an ATOMS (adjustable transobturator male system) device implanted to control stress urinary incontinence after prostate surgery. After implantation, 52.5% of the patients reported zero leakage and 39.9% reported only mild incontinence. Our results show that this device can improve continence after prostate surgery and is also suitable in patients who underwent radiotherapy.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Marine protected area (MPAs) networks can buffer marine ecosystems from the impacts of climate change by allowing species to redistribute as conditions change and by reducing other stressors. There are, however, few examples where climate change has been considered in MPA network design. In this paper, we assess how climate change considerations were integrated into the design of a newly released MPA network in the Northern Shelf Bioregion in British Columbia, Canada, and then evaluate the resulting network against projected physical and biogeochemical changes and biological responses. We found that representation, replication, and size and spacing recommendations integrated into the design phase were met in most cases. Furthermore, despite varying degrees of projected changes in temperature, dissolved oxygen, and aragonite saturation across the MPA network, suitable habitat for demersal fish species is projected to remain in the network despite some redistribution among sites. We also found that mid-depth MPAs are particularly important for persistence, as fish are projected to move deeper to avoid warming in shallower areas. Our results highlight that a representative MPA network with adequate replication, that incorporates areas of varying climate change trajectory, should buffer against the impacts of climate change.

Abstract In this work, we introduce a 2D materials family with chemical formula MX2 (M={As, Sb, Bi} and X={S, Se, Te}) having a rectangular 2D lattice. This materials family has been predicted by systematic ab-initio structure search calculations in two dimensions. Using density-functional theory and many-body perturbation theory, we study the structural, vibrational, electronic, optical, and excitonic properties of the predicted MX2 family. Our calculations reveal that the predicted SbX2 and BiX2 monolayers are stable while the AsX 2 layers exhibit an in-plane ferroelectric instability. All materials display strong excitonic effects and good optical absorption within the infrared-to-visible range. Hence, these monolayers can harvest solar energy and serve in optoelectronics applications. Furthermore, our results indicate that exfoliation of the predicted MX2 monolayers from their bulk counterparts is experimentally viable.

Abstract Seed‐based restoration of wetlands is often necessary to improve important ecosystem functions (e.g., invasion resistance and habitat provisioning) and meet society's need for wetland ecosystem services such as supporting recreational activities and improving water quality. However, persistent questions remain about the composition and sowing density of seed mixes needed to restore robust native wetland plant communities. In Great Salt Lake wetlands (Utah, USA), the revegetation of native species is crucial to recovering critical habitat and preventing reinvasion of the invasive, non‐native grass Phragmites australis and other invasive species (e.g., Typha spp.). In greenhouse and field experiments, we investigated the effects of seed mix composition and sowing density on plant community reassembly. We predicted that seed mixes containing native forb species with resource‐preempting traits (e.g., rapid seedling emergence and high aboveground growth rate) and high sowing densities (>5500 pure live seed m−2), would increase native plant light acquisition and establishment, thereby limiting invasive species. To our surprise, the effect of seed mix composition on native plant performance (cover and biomass) varied among the experiments, with distinct differences between plant functional groups arising. Native forb species had the highest performance in the greenhouse, but native grasses performed better in the field. Although multiple seed mix compositions show promise for establishing high native cover and biomass, these mixes may not always suppress invasive species. Interestingly, seed mix composition most often affected plant performance independent of sowing density. However, in one greenhouse experiment, we found that only slow‐growing mixes required a high sowing density to maximize native cover, an indication that the ideal sowing density may depend on the seed mix composition. Our research also supports the idea that in addition to reducing propagules of invasive species via appropriate management strategies, the application of higher sowing densities (>5500 pure live seed m−2) may lead to more favorable outcomes when a high density of invasive plant seeds remains or stressful field conditions are present. This research contributes to knowledge of plant community reestablishment in wetlands and demonstrates how seed‐based restoration strategies can catalyze native species revegetation and, in some situations, reduce the cover of invasive species.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Introduction: Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation in vitro and hypothesized that it would be correlated with poor response in human derived models and human tissues. Methods: Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured. Results: Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01). Conclusion: ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.

Objectives To describe opportunities and challenges experienced from the four pharmacoepidemiological database studies included in the rivaroxaban post authorisation safety study (PASS) programme and propose ways to maximise the value of population-based observational research when addressing regulatory requirements.Design PASS programme of rivaroxaban carried out as part of the regulatory postapproval commitment to the European Medicines Agency.Setting Clinical practice in Germany, the Netherlands, Sweden and the UK (electronic health records)—undertaken by pharmacoepidemiology research teams using country-specific databases with different coding structures.Participants 355 152 patients prescribed rivaroxaban and 338 199 patients prescribed vitamin K antagonists.Results Two major challenges that were encountered throughout the lengthy PASS programme were related to: (1) finalising country-tailored study designs before the extent of rivaroxaban uptake was known, and (2) new research questions that arose during the programme (eg, those relating to an evolving prescribing landscape).Recommendations We advocate the following strategies to help address these major challenges (should they arise in any future PASS): conducting studies based on a common data model that enable the same analytical tools to be applied when using different databases; maintaining early, clear, continuous communication with the regulator (including discussing the potential benefit of studying drug use as a precursor to planning a safety study); consideration of adaptive designs whenever uncertainty exists and following an initial period of data collection; and setting milestones for the review of study objectives.

Male stress urinary incontinence is a debilitating condition, which can occur after prostate surgery. In persistent cases, surgery is indicated and a number of options are available. This includes one of the male slings, Adjustable transobturator male system (ATOMSTM, A.M.I, Austria). There are now an increasing number of studies published. This review provides an overview of the current status of this implant device including technical considerations, surgical outcomes and potential advantages and disadvantages compared to alternatives such as the artificial urinary sphincter.

Abstract Background The COVID-19 pandemic involved a rapid change to the working conditions of all healthcare workers (HCW), including those in primary care. Organizational responses to the pandemic, including a shift to virtual care, changes in staffing, and reassignments to testing-related work, may have shifted more burden to these HCWs, increasing their burnout and turnover intent, despite their engagement to their organization. Our objectives were (1) to examine changes in burnout and intent to leave rates in VA primary care from 2017–2020 (before and during the pandemic), and (2) to analyze how individual protective factors and organizational context affected burnout and turnover intent among VA primary care HCWs during the early months of the pandemic. Methods We analyzed individual- and healthcare system-level data from 19,894 primary care HCWs in 139 healthcare systems in 2020. We modeled potential relationships between individual-level burnout and turnover intent as outcomes, and individual-level employee engagement, perceptions of workload, leadership, and workgroups. At healthcare system-level, we assessed prior-year levels of burnout and turnover intent, COVID-19 burden (number of tests and deaths), and the extent of virtual care use as potential determinants. We conducted multivariable analyses using logistic regression with standard errors clustered by healthcare system controlled for individual-level demographics and healthcare system complexity. Results In 2020, 37% of primary care HCWs reported burnout, and 31% reported turnover intent. Highly engaged employees were less burned out (OR = 0.57; 95% CI 0.52–0.63) and had lower turnover intent (OR = 0.62; 95% CI 0.57–0.68). Pre-pandemic healthcare system-level burnout was a major predictor of individual-level pandemic burnout (p = 0.014). Perceptions of reasonable workload, trustworthy leadership, and strong workgroups were also related to lower burnout and turnover intent (p

Abstract Background Regular participation in cervical cancer screening is critical to reducing mortality. Although certain sociodemographic factors are known to be associated with one-time participation in screening, little is known about other factors that could be related to regular participation. Therefore, this study evaluated the association between health-related behavioral factors and regular participation in cervical cancer screening. Methods The Lifelines population-based cohort was linked to data for cervical cancer screening from the Dutch Nationwide Pathology Databank. We included women eligible for all four screening rounds between 2000 and 2019, classifying them as regular (4 attendances), irregular (1–3 attendances), and never participants. Multinomial logistic regression was performed to evaluate the association between behavioral factors and participation regularity, with adjustment made for sociodemographic factors. Results Of the 48,325 included women, 55.9%, 35.1%, and 9% were regular, irregular, and never screening participants. After adjustment for sociodemographic factors, the likelihood of irregular or never screening participation was increased by smoking, obesity, marginal or inadequate sleep duration, alcohol consumption and low physical activity, while it was decreased by hormonal contraception use. Conclusion An association exists between unhealthy behavioral factors and never or irregular participation in cervical cancer screening.

The COVID-19 pandemic has had a significant impact on healthcare systems worldwide, including the postponing or canceling of appointments and procedures for type 2 diabetes (T2D) care by general practitioners (GPs) in the Netherlands. The aim of this study was to investigate the impact of the COVID-19 pandemic on primary healthcare use and clinical measurements for people with T2D. Additionally, we aimed to determine if changes were observed among specific risk groups: (1) persons 70 years or older, or below 70 years, (2) patients who were meeting their HbA1c targets and those who were not, and (3) patients with high-risk and non-high-risk T2D. This retrospective cohort study among persons with T2D was conducted using data from the DIAbetes MANagement and Treatment (DIAMANT) data infrastructure, deriving data from electronic medical records of Dutch GPs. The study assessed GP visit counts, and counts and values of clinical measurements, including hemoglobin A1c (HbA1c), body mass index (BMI), low-density lipoprotein (LDL) cholesterol, and systolic blood pressure (SBP). Adjusted negative binomial (NB) regression and generalized estimating equations (GEE) models were used to estimate GP visit counts and population averages of clinical measurements, respectively, comparing 2019 (pre-pandemic) with 2020 (during the pandemic). Changes in specific groups were examined by stratifying outcomes for the aforementioned subgroups. The cohort consisted of 182,048 patients with T2D (47% female, mean age 69 ± 13 years) on 1 March 2019, of which 168,097 persons (92%) still contributed follow-up data in 2020. We observed an increase in total GP visits in 2020, with an adjusted rate ratio (RR) of 1.09 (95% CI 1.08–1.09). The frequency increased for office visits (RR 1.06; 1.06–1.07) and phone calls (RR 1.33; 1.31–1.35) but remained stable for home visits (RR 1.02; 0.99–1.04). On both population and individual levels, HbA1c values increased in 2020 by 1.65 (1.59–1.70) mmol/mol compared to 2019. Observed changes in 2020 for BMI, LDL, and SBP values were also statistically significant but small. Subgroup stratifications showed higher scores of all clinical measurements in younger persons (

Abstract Background People living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations. Methods Persons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1–7, 8–14, 15–30, 31–180 and 181–365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome. Results 8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease [range of HR: from 15.3 (95% confidence interval 11.8–20.0) in days 1–7 to 1.3 (1.0–1.8) in days 181–365]. After a moderate exacerbation, the risk was increased over the first 180 days [HR 2.5 (1.3–4.8) in days 1–7 to 1.6 (1.3–2.1) in days 31–180]. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation [HR 48.6 (36.9–64.0) in days 1–7 down to 1.6 (1.0–2.6) in days 181–365]. Increase in risk concerned all categories of severe CV events. Conclusions Among incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.

Abstract The nasal and bronchial epithelium are unified parts of the respiratory tract that are affected in the monogenic disorder cystic fibrosis (CF). Recent studies have uncovered that nasal and bronchial tissues exhibit intrinsic variability, including differences in mucociliary cell composition and expression of unique transcriptional regulatory proteins which relate to germ layer origin. In the present study, we explored whether intrinsic differences between nasal and bronchial epithelial cells persist in cell cultures and affect epithelial cell functioning in CF. Comparison of air–liquid interface (ALI) differentiated epithelial cells from subjects with CF revealed distinct mucociliary differentiation states of nasal and bronchial cultures. Moreover, using RNA sequencing we identified cell type-specific signature transcription factors in differentiated nasal and bronchial epithelial cells, some of which were already poised for expression in basal progenitor cells as evidenced by ATAC sequencing. Analysis of differentiated nasal and bronchial epithelial 3D organoids revealed distinct capacities for fluid secretion, which was linked to differences in ciliated cell differentiation. In conclusion, we show that unique phenotypical and functional features of nasal and bronchial epithelial cells persist in cell culture models, which can be further used to investigate the effects of tissue-specific features on upper and lower respiratory disease development in CF.

Abstract Background In care substitution services, medical specialists offer brief consultations to provide general practitioners (GPs) with advice on diagnosis, treatment, or hospital referral. When GPs serve as gatekeepers to secondary care, these regional services could reduce pressures on healthcare systems. The aim is to determine the impact of implementing a care substitution service for dermatology, orthopaedics, and cardiology on the hospital referral rate, health care costs, and patient satisfaction. Methods A before-after study was used to evaluate hospital referral rates and health care costs during a follow-up period of 1 year. The study population comprised patients with eligible International Classification of Primary Care codes for referral to the care substitution service (only dermatology, orthopaedic, cardiology indications), as pre-defined by GPs and medical specialists. We compared referral rates before and after implementation by χ2 tests and evaluated patient preference by qualitative analysis. Results In total, 4,930 patients were included, 2,408 before and 2,522 after implementation. The care substitution service decreased hospital referrals during the follow-up period from 15 to 11%. The referral rate decreased most for dermatology (from 15 to 9%), resulting in a cost reduction of €10.59 per patient, while the other two specialisms experienced smaller reductions in referral rates. Patients reported being satisfied, mainly because of the null cost, improved organisation, improved care, and positive experience of the consultation. Conclusions The care substitution service showed promise for specialisms that require fewer hospital facilities, as exemplified by dermatology.

Abstract Background The Veterans Affairs (VA) Clinical Resource Hub (CRH) program aims to improve patient access to care by implementing time-limited, regionally based primary or mental health staffing support to cover local staffing vacancies. VA’s Office of Primary Care (OPC) designed CRH to support more than 1000 geographically disparate VA outpatient sites, many of which are in rural areas, by providing virtual contingency clinical staffing for sites experiencing primary care and mental health staffing deficits. The subsequently funded CRH evaluation, carried out by the VA Primary Care Analytics Team (PCAT), partnered with CRH program leaders and evaluation stakeholders to develop a protocol for a six-year CRH evaluation. The objectives for developing the CRH evaluation protocol were to prospectively: 1) identify the outcomes CRH aimed to achieve, and the key program elements designed to achieve them; 2) specify evaluation designs and data collection approaches for assessing CRH progress and success; and 3) guide the activities of five geographically dispersed evaluation teams. Methods The protocol documents a multi-method CRH program evaluation design with qualitative and quantitative elements. The evaluation’s overall goal is to assess CRH’s return on investment to the VA and Veterans at six years through synthesis of findings on program effectiveness. The evaluation includes both observational and quasi-experimental elements reflecting impacts at the national, regional, outpatient site, and patient levels. The protocol is based on program evaluation theory, implementation science frameworks, literature on contingency staffing, and iterative review and revision by both research and clinical operations partners. Discussion Health systems increasingly seek to use data to guide management and decision-making for newly implemented clinical programs and policies. Approaches for planning evaluations to accomplish this goal, however, are not well-established. By publishing the protocol, we aim to increase the validity and usefulness of subsequent evaluation findings. We also aim to provide an example of a program evaluation protocol developed within a learning health systems partnership.

Abstract Epigenetic remodeling is emerging as a critical process for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Genetics alone fails to explain the etiology of ALS, the investigation of the epigenome might therefore provide novel insights into the molecular mechanisms of the disease. In this study, we interrogated the epigenetic landscape in peripheral blood mononuclear cells (PBMCs) of familial ALS (fALS) patients with either chromosome 9 open reading frame 72 (C9orf72) or superoxide dismutase 1 (SOD1) mutation and aimed to identify key epigenetic footprints of the disease. To this end, we used an integrative approach that combines chromatin immunoprecipitation targeting H3K27me3 (ChIP-Seq) with the matching gene expression data to gain new insights into the likely impact of blood-specific chromatin remodeling on ALS-related molecular mechanisms. We demonstrated that one of the hub molecules that modulates changes in PBMC transcriptome in SOD1-mutant ALS patients is ATF3, which has been previously reported in an SOD1 G93A mouse model. We also identified potential suppression of SNAP25, with impaired ATF3 signaling in SOD1-mutant ALS blood. Together, our study shed light on the mechanistic underpinnings of SOD1 mutations in ALS.

Abstract Background ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. Results We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. Conclusion Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer’s and Parkinson’s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.

Abstract CD8+ T cell tissue resident memory (TRM) cells are especially suited to control pathogen spread at mucosal sites. However, their maintenance in lung is short-lived. TCR-dependent NFkB signaling is crucial for T cell memory but how and when NFkB signaling modulates tissue resident and circulating T cell memory during the immune response is unknown. Here, we find that enhancing NFkB signaling in T cells once memory to influenza is established, increases pro-survival Bcl-2 and CD122 levels thus boosting lung CD8+ TRM maintenance. By contrast, enhancing NFkB signals during the contraction phase of the response leads to a defect in CD8+ TRM differentiation without impairing recirculating memory subsets. Specifically, inducible activation of NFkB via constitutive active IKK2 or TNF interferes with TGFβ signaling, resulting in defects of lung CD8+ TRM imprinting molecules CD69, CD103, Runx3 and Eomes. Conversely, inhibiting NFkB signals not only recovers but improves the transcriptional signature and generation of lung CD8+ TRM. Thus, NFkB signaling is a critical regulator of tissue resident memory, whose levels can be tuned at specific times during infection to boost lung CD8+ TRM.

Abstract Background For accurate thoracic and abdominal radiotherapy, inter- and intrafractional geometrical uncertainties need to be considered to enable accurate margin sizes. We aim to quantify interfractional diaphragm and abdominal organ position variations, and intrafractional diaphragm motion in a large multicenter cohort of pediatric cancer patients (

Abstract Background Postoperative rehabilitation after primary total hip arthroplasty (p-THA) differs between the Netherlands and Germany. Aim is to compare clinical effectiveness and to get a first impression of cost effectiveness of Dutch versus German usual care after p-THA. Methods A transnational prospective controlled observational trial. Clinical effectiveness was assessed with self-reported questionnaires and functional tests. Measurements were taken preoperatively and 4 weeks, 12 weeks, and 6 months postoperatively. For cost effectiveness, long-term economic aspects were assessed from a societal perspective. Results 124 working-age patients finished the measurements. German usual care leads to a significantly larger proportion (65.6% versus 47.5%) of satisfied patients 12 weeks postoperatively and significantly better self-reported function and Five Times Sit-to-Stand Test (FTSST) results. German usual care is generally 45% more expensive than Dutch usual care, and 20% more expensive for working-age patients. A scenario analysis assumed that German patients work the same number of hours as the Dutch, and that productivity costs are the same. This analysis revealed German care is still more expensive but the difference decreased to 8%. Conclusions German rehabilitation is clinically advantageous yet more expensive, although comparisons are less straightforward as the socioeconomic context differs between the two countries. Trial registration The study is registered in the German Registry of Clinical Trials (DRKS00011345, 18/11/2016).

Purpose/background: The aim of this study was to evaluate pencil beam scanning (PBS) proton therapy (PT) in deep inspiration breath-hold (DIBH) for mediastinal lymphoma patients, by retrospectively evaluating plan robustness to the clinical target volume (CTV) and organs at risk (OARs) on repeated CT images acquired throughout treatment. Methods: Sixteen mediastinal lymphoma patients treated with PBS-PT in DIBH were included. Treatment plans (TPs) were robustly optimized on the CTV (7 mm/4.5%). Repeated verification CTs (vCT) were acquired during the treatment course, resulting in 52 images for the entire patient cohort. The CTV and OARs were transferred from the planning CT to the vCTs with deformable image registration and the TPs were recalculated on the vCTs. Target coverage and OAR doses at the vCTs were compared to the nominal plan. Deviation in lung volume was also calculated. Results: The TPs demonstrated high robust target coverage throughout treatment with D98%,CTV deviations within 2% for 14 patients and above the desired requirement of 95% for 49/52 vCTs. However, two patients did not achieve a robust dose to CTV due to poor DIBH reproducibility, with D98%,CTV at 78 and 93% respectively, and replanning was performed for one patient. Adequate OAR sparing was achieved for all patients. Total lung volume variation was below 10% for 39/52 vCTs. Conclusion: PBS PT in DIBH is generally a robust technique for treatment of mediastinal lymphomas. However, closely monitoring the DIBH-reproducibility during treatment is important to avoid underdosing CTV and achieve sufficient dose-sparing of the OARs.

Introduction Pulmonary fibrosis is a severe disease which can be familial. A genetic cause can only be found in ∼40% of families. Searching for shared novel genetic variants may aid the discovery of new genetic causes of disease. Methods Whole-exome sequencing was performed in 152 unrelated patients with a suspected genetic cause of pulmonary fibrosis from the St Antonius interstitial lung disease biobank. Variants of interest were selected by filtering for novel, potentially deleterious variants that were present in at least three unrelated pulmonary fibrosis patients. Results The novel c.586G>A p.(E196K) variant in the ZCCHC8 gene was observed in three unrelated patients: two familial patients and one sporadic patient, who was later genealogically linked to one of the families. The variant was identified in nine additional relatives with pulmonary fibrosis and other telomere-related phenotypes, such as pulmonary arterial venous malformations, emphysema, myelodysplastic syndrome, acute myeloid leukaemia and dyskeratosis congenita. One family showed incomplete segregation, with absence of the variant in one pulmonary fibrosis patient who carried a PARN variant. The majority of ZCCHC8 variant carriers showed short telomeres in blood. ZCCHC8 protein was located in different lung cell types, including alveolar type 2 (AT2) pneumocytes, the culprit cells in pulmonary fibrosis. AT2 cells showed telomere shortening and increased DNA damage, which was comparable to patients with sporadic pulmonary fibrosis and those with pulmonary fibrosis carrying a telomere-related gene variant, respectively. Discussion The ZCCHC8 c.586G>A variant confirms the involvement of ZCCHC8 in pulmonary fibrosis and short-telomere syndromes and underlines the importance of including the ZCCHC8 gene in diagnostic gene panels for these diseases.

Background and Purpose: Hippocampal-sparing (HS) is a method that can potentially reduce late cognitive complications for pediatric medulloblastoma (MB) patients treated with craniospinal proton therapy (PT). The aim of this study was to investigate robustness and dosimetric plan verification of pencil beam scanning HS PT. Materials and Methods: HS and non-HS PT plans for the whole brain part of craniospinal treatment were created for 15 pediatric MB patients. A robust evaluation of the plans was performed. Plans were recalculated in a water phantom and measured field-by-field using an ion chamber detector at depths corresponding to the central part of hippocampi. All HS and non-HS fields were measured with the standard resolution of the detector and in addition 16 HS fields were measured with high resolution. Measured and planned dose distributions were compared using gamma evaluation. Results: The median mean hippocampus dose was reduced from 22.9 Gy (RBE) to 8.9 Gy (RBE), while keeping CTV V95% above 95 % for all nominal HS plans. HS plans were relatively robust regarding hippocampus mean dose, however, less robust regarding target coverage and maximum dose compared to non-HS plans. For standard resolution measurements, median pass rates were 99.7 % for HS and 99.5 % for non-HS plans (p

Organizations conducting global environmental assessments (GEAs) face the challenge of not only producing trustworthy and policy-relevant knowledge but also recruiting and training experts to conduct these GEAs. These experts must acquire the skills and competencies needed to produce knowledge assessments. By adopting an institutional approach, this paper explores IPBES’s epistemic infrastructure that aims to communicate and form the expertise that is needed to conduct its assessments. The empirical material consists of IPBES’s educational material, which teaches new experts how to perform the assessment. The analysis finds three crucial tasks that experts introduced in the assessments are expected to learn and perform. The paper concludes by discussing the broader importance of the findings that organizations that conduct GEAs are not passive intermediaries of knowledge but instead, through their epistemic infrastructure, generate ways to understand and navigate the world, both for those who create and those who receive the assessment report.

Abstract Recently, rapidly increased demands of integration and miniaturization continuously challenge energy densities of dielectric capacitors. New materials with high recoverable energy storage densities become highly desirable. Here, by structure evolution between fluorite HfO2 and perovskite hafnate, we create an amorphous hafnium-based oxide that exhibits the energy density of ~155 J/cm3 with an efficiency of 87%, which is state-of-the-art in emergingly capacitive energy-storage materials. The amorphous structure is owing to oxygen instability in between the two energetically-favorable crystalline forms, in which not only the long-range periodicities of fluorite and perovskite are collapsed but also more than one symmetry, i.e., the monoclinic and orthorhombic, coexist in short range, giving rise to a strong structure disordering. As a result, the carrier avalanche is impeded and an ultrahigh breakdown strength up to 12 MV/cm is achieved, which, accompanying with a large permittivity, remarkably enhances the energy storage density. Our study provides a new and widely applicable platform for designing high-performance dielectric energy storage with the strategy exploring the boundary among different categories of materials.

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Abstract Background Use of the direct oral anticoagulant rivaroxaban has strongly increased in Europe since its market approval for non-valvular atrial fibrillation in 2011. Patients characteristics of rivaroxaban initiators may have changed over time but this has not been investigated so far. Objective We aimed to describe time trends of patient baseline characteristics among new rivaroxaban users with non-valvular atrial fibrillation from 2011 to 2016/17 in two European countries. Methods We used data from Germany (German Pharmacoepidemiological Research Database) and the Netherlands (PHARMO Database Network). We included new rivaroxaban users with (i) a first dispensing between 2011 and 2016/17, (ii) ≥ 2 years of age, and (iii) a diagnosis of non-valvular atrial fibrillation and described their baseline medication and comorbidity prior to starting rivaroxaban stratified by year of inclusion. Results Overall, 130,652 new rivaroxaban users were included during the study period (Germany: N = 127,743, the Netherlands: N = 2909). The sex ratio and median age remained relatively stable over time. The proportion of patients without prior use of oral anticoagulants before initiation of rivaroxaban increased in both countries between 2011 and 2016/17 (Germany: from 51 to 76%, the Netherlands: from 57 to 85%). In Germany, we observed a relative decrease by 27% in the proportion of new rivaroxaban users with a history of ischemic stroke and by 18% in the proportion with a transient ischemic attack at baseline. No such a pattern was observed in the Netherlands. The proportion of patients with heart failure at baseline showed a three-fold increase in the Netherlands, while there was a relative decrease by 12% in Germany. Conclusions Patient characteristics of new rivaroxaban users with non-valvular atrial fibrillation changed between 2011 and 2016/17, but changes differed between countries. These patterns have methodological implications. They have to be considered in the interpretation of observational studies comparing effectiveness and safety of oral anticoagulants, especially regarding potential bias due to unmeasured confounding.

Abstract Objective Social functioning is an important factor in the evaluation of postoperative health‐related quality of life (HRQoL) for pituitary adenoma patients. In a prospective cohort study multidimensional HRQoL of non‐functioning (NFA) and functioning (FA) pituitary adenoma patients were evaluated following endoscopic endonasal surgery using the endoscopic endonasal sinus and skull base surgery questionnaire (EES‐Q). Methods Prospectively, 101 patients were included. The EES‐Q was completed preoperatively and postoperatively (2 weeks, 3 months, 1 year). Sinonasal complaints were completed daily during the first week postoperatively. Preoperative and postoperative scores were compared. A generalized estimating equation (uni‐ and multivariate) analysis was performed to identify significant HRQoL changes related to selected covariates. Results Two weeks postoperatively, physical (p

Rustrela virus (RusV) was detected in the brains of 27 out of 29 domestic cats with ‘staggering disease’, but not of 29 control cats. This suggests RusV as the long-sought causative agent of ‘staggering disease’, which had been obscure for 50 years.

Objective: CR1447, a novel transdermal formulation of 4-hydroxytestosterone, has aromatase-inhibiting and androgen receptor (AR)-modulating properties (IC50 4.4 nM) with antitumor effects against AR-positive tumor cells in vitro. This trial investigated the efficacy and safety of CR1447 for patients with metastatic estrogen receptor-positive (A) and AR-positive triple-negative breast cancers (B). Design and methods: (A) included patients with at most one prior endocrine therapy line without progression ≥6 months, whereas (B) included patients with ≤2 prior chemotherapy lines, all displaying advanced signs of disease. The primary endpoint was disease control at week 24 (DC24). The null hypothesis was DC24 ≤30% (A) and ≤15% (B). Thirty-seven patients were recruited (29 in (A) and 8 in (B)); accrual was stopped following an interim analysis demonstrating futility in (A) and slow accrual in (B). Results: DC24 was attained in 5/21 (95% CI: 8.2–47.2) patients in (A) and none in (B). The median progression-free survival was 5.1 months (95% CI: 2.5–5.6) in (A) and 2.5 months (95% CI: 0.7–2.6) in (B). The median overall survival was 24.6 months (95% CI: 22.9–not applicable) in (A) and 10.8 months (95% CI: 3.3–10.9) in (B). CR1447 had a favorable safety profile without treatment-related grade 3–5 toxicities in (A). Especially no side effects linked to androgenic effects were observed. Conclusions: Despite this trial being negative, the 24% DC24 rate in a second-line setting, and the prolonged partial response experienced by a patient, indicate activity. Further evaluation of CR1447 in endocrine-sensitive patients or combination trials appears warranted.

To prevent floods from becoming disasters, social vulnerability must be integrated into flood risk management. This Comment advocates that the welfare of different societal groups should be included by adding recovery capacity, impacts of beyond-design events, and distributional impacts.

Amyotrophic Lateral Sclerosis related TDP-43 protein translocates to stress granules with a concomitant reduction in mobility. Here, the authors use single molecule tracking and find a stress-induced reduction in TDP-43 mobility also in the cytoplasm potentially relevant for TDP-43 aggregation.

Abstract Background Children with cerebral palsy (CP) are at high risk for dental caries. Alteration of some salivary properties encountered among them compared to healthy children, could play a role in this elevated risk. Objectives The aim of the present study was to assess salivary physicochemical properties; including total antioxidant (TAC), flow rate, viscosity, pH and buffering capacity, as well as Streptococcus mutans level among children with CP, also to correlate these variables to their caries experience. Materials and methods This case control study included 80 children with CP, study group (SG) and matched number of healthy children for control group (CG). Interview-based questionnaire, clinical examination, salivary biochemical and microbiological investigations using MALDI-TOF were done. Results In SG, the caries experience in primary teeth dmft and S. mutans log value were significantly higher than CG (P = 0.039, P = 0.002) while unstimulated salivary flow rate, buffering capacity and salivary TAC were significantly lower (P

In this study the authors investigate household transmission of SARS-CoV-2 in Norway. They find that the secondary attack rate was higher for Omicron than Delta, but that among three-dose vaccinated contacts the secondary attack rate was lower for both variants compared to contacts with two doses.

Ferroelectric hafnium and zirconium oxides have undergone rapid scientific development over the last decade, pushing them to the forefront of ultralow-power electronic systems. Maximizing the potential application in memory devices or supercapacitors of these materials requires a combined effort by the scientific community to address technical limitations, which still hinder their application. Besides their favorable intrinsic material properties, HfO2–ZrO2 materials face challenges regarding their endurance, retention, wake-up effect, and high switching voltages. In this Roadmap, we intend to combine the expertise of chemistry, physics, material, and device engineers from leading experts in the ferroelectrics research community to set the direction of travel for these binary ferroelectric oxides. Here, we present a comprehensive overview of the current state of the art and offer readers an informed perspective of where this field is heading, what challenges need to be addressed, and possible applications and prospects for further development.

IntroductionMachine perfusion is increasingly being utilized in liver transplantation in lieu of traditional cold static organ preservation. Nevertheless, better understanding of the molecular mechanisms underlying the ischemia-reperfusion injury (IRI) during ex vivo perfusion is necessary to improve the viability of liver grafts after transplantation using machine perfusion technology. Since key cellular signaling pathways involved in hepatic IRI may allow a chance for designing a promising approach to improve the clinical outcomes from this technology, we determined how warm ischemia time (WIT) during procurement affects the activity of mitogen-activated protein kinase (MAPK) and perfusate concentration of cytokines in an ex vivo rat liver machine perfusion model.MethodsMale Sprague-Dawley rats underwent in situ hepatic ischemia with varying WIT (0, 10, 20, 30 min, n = 5 each), and subsequently 3 h of cold ischemia time and 2 h of machine perfusion prior to determining the degree of MAPK activation-phosphorylation and cytokine concentration in liver tissue and perfusates, respectively.ResultsOur data revealed a strong correlation between incremental WIT and a series of liver injury markers, and that prolonged WIT increases ERK1/2 and p54 JNK phosphorylation during machine perfusion. Notably, specific cytokine levels (MCP-1, MIP-2, GRO/KC, IL-10, and IL-5) were inversely correlated with the phosphorylation levels of ERK1/2, p38 MAPK, and p46/p54 JNK.DiscussionThese results suggest that MAPK activation, specifically ERK1/2 and p54 JNK phosphorylation, have potential as a biomarker for hepatic IRI pathophysiology during machine perfusion. Elucidation of their functional significance may lead to designing a novel strategy to increase the clinical benefit of machine perfusion.

BackgroundDysregulation of the immune system in amyotrophic lateral sclerosis (ALS) includes changes in T-cells composition and infiltration of T cells in the brain and spinal cord. Recent studies have shown that cytotoxic T cells can directly induce motor neuron death in a mouse model of ALS and that T cells from ALS patients are cytotoxic to iPSC-derived motor neurons from ALS patients. Furthermore, a clonal expansion to unknown epitope(s) was recently found in familial ALS and increased peripheral and intrathecal activation of cytotoxic CD8+ T cells in sporadic ALS.ResultsHere, we show an increased activation of peripheral T cells from patients with sporadic ALS by IL-2 treatment, suggesting an increase of antigen-experienced T cells in ALS blood. However, a putative antigen for T-cell activation in ALS has not yet been identified. Therefore, we investigated if peptides derived from TDP-43, a key protein in ALS pathogenesis, can act as epitopes for antigen-mediated activation of human T cells by ELISPOT and flow cytometry. We found that TDP-43 peptides induced only a weak MHCI or MHCII-restricted activation of both naïve and antigen-experienced T cells from healthy controls and ALS patients. Interestingly, we found less activation in T cells from ALS patients to TDP-43 and control stimuli. Furthermore, we found no change in the levels of naturally occurring auto-antibodies against full-length TDP-43 in ALS.ConclusionOur data suggests a general increase in antigen-experienced T cells in ALS blood, measured by in-vitro culture with IL-2 for 14 days. Furthermore, it suggests that TDP-43 is a weak autoantigen.

ABSTRACT 16S-based sequencing provides broader information on the respiratory microbial community than conventional culturing. However, it (often) lacks species- and strain-level information. To overcome this issue, we used 16S rRNA-based sequencing results from 246 nasopharyngeal samples obtained from 20 infants with cystic fibrosis (CF) and 43 healthy infants, which were all 0 to 6 months old, and compared them to both standard (blind) diagnostic culturing and a 16S-sequencing-informed “targeted” reculturing approach. Using routine culturing, we almost uniquely detected Moraxella catarrhalis, Staphylococcus aureus, and Haemophilus influenzae (42%, 38%, and 33% of samples, respectively). Using the targeted reculturing approach, we were able to reculture 47% of the top-5 operational taxonomical units (OTUs) in the sequencing profiles. In total, we identified 60 species from 30 genera with a median of 3 species per sample (range, 1 to 8). We also identified up to 10 species per identified genus. The success of reculturing the top-5 genera present from the sequencing profile depended on the genus. In the case of Corynebacterium being in the top 5, we recultured them in 79% of samples, whereas for Staphylococcus, this value was only 25%. The success of reculturing was also correlated with the relative abundance of those genera in the corresponding sequencing profile. In conclusion, revisiting samples using 16S-based sequencing profiles to guide a targeted culturing approach led to the detection of more potential pathogens per sample than conventional culturing and may therefore be useful in the identification and, consequently, treatment of bacteria considered relevant for the deterioration or exacerbation of disease in patients like those with CF. IMPORTANCE Early and effective treatment of pulmonary infections in cystic fibrosis is vital to prevent chronic lung damage. Although microbial diagnostics and treatment decisions are still based on conventional culture methods, research is gradually focusing more on microbiome and metagenomic-based approaches. This study compared the results of both methods and proposed a way to combine the best of both worlds. Many species can relatively easily be recultured based on the 16S-based sequencing profile, and it provides more in-depth information about the microbial composition of a sample than that obtained through routine (blind) diagnostic culturing. Still, well-known pathogens can be missed by both routine diagnostic culture methods as well as by targeted reculture methods, sometimes even when they are highly abundant, which may be a consequence of either sample storage conditions or antibiotic treatment at the time of sampling.

IntroductionCoastal estuarine wetlands provide important habitats for a variety of endemic flora and fauna but are particularly vulnerable to biological invasions. Regular monitoring of changes in these vulnerable wetlands has become increasingly important for effective management, especially considering threats from climate change effects and human disturbance. Historical analyzes of plant invasions may guide targeted management strategies to eradicate harmful species. Estimating the distribution of invasive species has never been more accessible with the improved availability of high-resolution data and innovations in remote sensing, estimating the distribution of invasive species has never been more accessible.MethodsWe assessed the spread of non-native Phragmites australis subsp. australis in Suisun Marsh on the upper San Francisco Estuary, one of the largest brackish coastal wetlands in North America. Suisun Marsh consists of managed and tidal wetlands, and efforts have been made to control invasive P. australis on the managed wetlands to support habitat values for wildlife. We used remote-sensing analyzes of publicly available, biennial color-infrared images taken by the National Agriculture Imagery Program (NAIP) to map the expansion of invasive P. australis across two decades. We generated random forest classifications of representative images to map the distribution of P. australis, then calculated a variety of metrics describing the rate and spatial extent of the P. australis spread. Additionally, we ran generalized linear models to examine factors related to the growth of P. australis.ResultsOur classifications yielded accuracies of over 90% and showed a 234% (1,084 ha) increase in P. australis between 2003 and 2018. The expansion rate of P. australis patches averaged 1.32 m/year (±0.53 SD) which is higher than most reported in the literature. We found that P. australis expansion in managed areas within levees was significantly correlated with invasion in tidal areas outside the levees on the same parcel and also related to its spread on adjacent parcels.DiscussionOur findings suggest that despite individual landowner management efforts, P. australis has continued to expand substantially throughout Suisun Marsh. Future efforts to treat invasive P. australis may require emphasizing adaptive, collaborative management rather than individual management strategies to ensure the invasive species is eradicated on a large scale to preserve the valued ecosystem functions.

The proximity of the Large and Small Magellanic Clouds (LMC and SMC) provides the opportunity to study the impact of dwarf–dwarf interactions on their mass assembly with a unique level of detail. To this end, we analyze two-filter broadband imaging of 83 Hubble Space Telescope (HST) pointings covering 0.203 deg ^2 toward the SMC, extending out to ∼3.5 kpc in projection from its optical center. Lifetime star formation histories (SFHs) fit to each pointing independently reveal an outside-in age gradient such that fields in the SMC outskirts are older on average. We measure radial gradients of the look-back time to form 90%, 75%, and 50% of the cumulative stellar mass for the first time, finding δ ( τ _90 , τ _75 , τ _50 )/ δ R = (0.61 ${}_{-0.07}^{+0.08}$ , ${0.65}_{-0.08}^{+0.09}$ , ${0.82}_{-0.16}^{+0.12}$ ) Gyr kpc ^−1 assuming PARSEC evolutionary models and a commonly used elliptical geometry of the SMC, although our results are robust to these assumptions. The wing of the SMC deviates from this trend, forming 25% of its cumulative mass over the most recent 3 Gyr owing to a best-fit star formation rate that remains approximately constant. Our results are consistent with chemodynamical evidence of a tidally stripped SMC component in the foreground and imply contributions to the observed SFH from multiple previous LMC–SMC interactions. We also compare our SMC SFH with results from a companion study of the LMC, finding that while the two galaxies present different internal, spatially resolved SFH trends, both the LMC and SMC have similar near-constant lifetime SFHs when viewed globally.