Single-nuclei sequencing of uterine serous carcinoma reveals racial differences in immune signaling.

Significant racial disparities exist between Black and White patients with uterine serous carcinoma (USC). While the reasons for these disparities are unclear, several studies have demonstrated significantly different rates of driver mutations between racial groups, including TP53. However, limited research has investigated the transcriptional differences of tumors or the composition of the tumor microenvironment (TME) between these groups. Here, we report the single-nuclei RNA-sequencing profiles of primary USC tumors from diverse racial backgrounds. We find that there are significant differences between the tumors of Black and White patients. Tumors from Black patients exhibited higher expression of specific genes associated with aggressiveness, such as PAX8, and axon guidance and synaptic signaling pathways. We also demonstrated that T cell populations are reduced in the tumor tissue compared to matched benign, while anti-inflammatory macrophage populations are retained within the TME. Furthermore, we investigated the connection between PAX8 overexpression and immunosuppression in USC through regulation of several cytokines and chemokines. Notably, we show that PAX8 activity can influence macrophage gene expression and protein secretion. These studies provide a detailed understanding of the USC transcriptome and TME, and identify differences in tumor biology from patients of different racial backgrounds.

Isotropy of Cosmic Rays beyond 10

We report an estimation of the injected mass composition of ultrahigh energy cosmic rays (UHECRs) at energies higher than 10 EeV. The composition is inferred from an energy-dependent sky distribution of UHECR events observed by the Telescope Array surface detector by comparing it to the Large Scale Structure of the local Universe. In the case of negligible extragalactic magnetic fields (EGMFs), the results are consistent with a relatively heavy injected composition at E∼10 EeV that becomes lighter up to E∼100 EeV, while the composition at E>100 EeV is very heavy. The latter is true even in the presence of highest experimentally allowed extragalactic magnetic fields, while the composition at lower energies can be light if a strong EGMF is present. The effect of the uncertainty in the galactic magnetic field on these results is subdominant.

The verification of the utility of a commercially available phantom combination for quality control in contrast-enhanced mammography.

Contrast-enhanced mammography is being increasingly implemented clinically, providing much improved contrast between tumour and background structures, particularly in dense breasts. Although CEM is similar to conventional mammography it differs via an additional exposure with high energy X-rays (≥ 40 kVp) and subsequent image subtraction. Because of its special operational aspects, the CEM aspect of a CEM unit needs to be uniquely characterised and evaluated. This study aims to verify the utility of a commercially available phantom set (BR3D model 020 and CESM model 022 phantoms (CIRS, Norfolk, Virginia, USA)) in performing key CEM performance tests (linearity of system response with iodine concentration and background subtraction) on two models of CEM units in a clinical setting. The tests were successfully performed, yielding results similar to previously published studies. Further, similarities and differences in the two systems from different vendors were highlighted, knowledge of which may potentially facilitate optimisation of the systems.

Trends and causes of maternal mortality in Indonesia: a systematic review.

BACKGROUND: The maternal mortality ratio (MMR) in Indonesia is among the highest in Southeast Asia. We aim to describe trends in the MMR and causes of maternal deaths in Indonesia over the past decades, regionally and nationally. METHODS: We performed a systematic review and conducted a search using PubMed, Embase, Global Health, CINAHL, Cochrane, Portal Garuda, and Google Scholar from the inception of the database to April 2023. We included all studies on the incidence and/or the causes of maternal deaths in Indonesia. The MMR was defined as the number of maternal deaths per 100,000 live births. Maternal death causes were assessed and reclassified according to the WHO International Classification of Disease Maternal Mortality (ICD-MM). RESULTS: We included 63 studies that reported the MMR (54 studies) and/or the causes of maternal deaths (44 studies) in Indonesia from 1970 to 2022, with a total of 254,796 maternal deaths. The national MMR declined from 450 to 249 (45%) between 1990 and 2020. Great differences in MMR exist across the country, with the lowest in Java-Bali and the highest (more than twice the national MMR) in Sulawesi and Eastern Indonesia. Between 1990 and 2022, the proportion of deaths due to hemorrhage and sepsis decreased, respectively from 48 to 18% and 15-5%, while the share of deaths due to hypertensive disorders and non-obstetric causes increased, respectively from 8 to 19% and 10-49%. CONCLUSION: Despite the steady decline of maternal deaths in Indonesia, it remains one of the highest in Southeast Asia, with enormous disparities within the country. Hypertensive disorders and non-communicable diseases make up a growing share of maternal deaths, making maternal death reduction strategies increasingly challenging. National Maternal Death Surveillance and Response needs to be prioritized to eliminate preventable maternal deaths in Indonesia. REGISTRATION OF SYSTEMATIC REVIEWS: PROSPERO, CRD42022320213.

Improving dependability in science: A critique on the psychometric qualities of the HiTOP psychosis superspectrum.

We reevaluated HiTOP's existing factor analytic evidence-base for a Psychosis (P) superspectrum as encompassing two psychosis-relevant subfactors ("spectra")-Thought Disorder (TD) and Detachment (D). We found that their data did not support P as a superspectrum with TD and D subfactors. Instead, TD contained both positive and negative symptoms of psychosis and emerged at the subfactor level. D did not target negative symptoms but, largely, disorders unrelated to psychosis and should not be placed under P. Determining if P is truly a superspectrum with psychosis TD and D subfactors will require factor analyses whose items are symptom-based and span the full range of psychopathology. Secondly, HiTOP authors state that TD and D provide a "nearly 2-fold" improvement in reliability over schizophrenia diagnoses but, after aligning the comparative study methodologies, this 2-fold improvement disappears. Finally, HiTOP's use of the term thought disorder is inconsistent with the ICD-11 and psychosis literature, in which it refers to formal thought disorder. We recommend that HiTOP (a) refer to P as a subfactor with positive and negative symptoms of psychosis until research indicates otherwise, (b) regularly rely on formal systematic reviews, (c) use appropriate reliability comparisons, (d) deconflate D with negative symptoms, and (e) rename TD.

50 GHz Four-Port Coupling-Reduced Probe Card Utilizing Pogo Pins Housed in Custom Metallic Socket.

A design for a pogo-pin probe card featuring a metallic socket is proposed to eliminate signal leakage and coupling loss in a multi-port environment. The proposed metallic pogo-pin socket includes a metal wall structure between adjacent pogo pins, ensuring complete isolation. This metal wall offers an advantage in removing coupling issues between pogo pins that can occur with typical dielectric pogo-pin sockets. The designed probe card is fabricated as a prototype and verified for its performance. Measurement results using a test through line show that coupled power is minimized, providing a low-loss transmission performance of -2.14 dB to an RF chip at 50 GHz, all within a compact size. Although the dielectric spacer used to secure the pogo pins allows for some leakage, it can maintain a low coupling performance of under -15 dB in the millimeter-wave band. The prototype probe card can deliver an RF signal to a 5G circuit with a low loss of -0.7 dB at 28 GHz and -1.9 dB at 39 GHz frequency. The designed probe card is capable of transmitting multiple RF signals to the RF system without signal distortion in a multi-port environment.

Gene expression in the dorsal root ganglion and the cerebrospinal fluid metabolome in polyneuropathy and opioid tolerance in rats.

First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.

Coherent amplitude modulation of continuous-wave light in cesium vapor.

We report on observations of coherent, sustained oscillations in the absorption of continuous-wave light at 388 nm that excites the 6S1/2 → 8P3/2 transition in cesium (Cs) vapor. The oscillation frequency is close to the spacing of hyperfine levels of the 8P3/2 level that are excited simultaneously by the 388 nm field. We observe a threshold behavior of the oscillation amplitude with pump power and suggest that the effect is associated with infrared directional emission due to amplified spontaneous emission (ASE) from the 8P3/2 → 8S1/2 transition that is assisted by retro-reflections from cell windows. The effect may be used to probe a lasing process in an atomic vapor, by checking the temporal properties of the pump field transmitted through the vapor.

Interventions that support novice nurses' transition into practice: A realist review.

BACKGROUND: Many transition-to-practice programs have been developed to support novice nurses during their first years into practice. These programs report improvements in retention, wellbeing and clinical competence, but the driving mechanisms of these interventions remain largely unclear. OBJECTIVE: To identify how transition-to-practice programs for novice nurses work and in what contexts they work successfully. METHODS: A realist review was conducted. Eligibility criteria included intervention studies aimed at novice nurses in their first two years of practice that reported outcomes on organizational or individual nurse level. The underlying theory of included transition-to-practice programs was extracted, and relevant contextual factors, mechanisms and outcomes were explored and synthesized into context-mechanism-outcome (CMO) configurations. The search was limited to studies between 2000 and 2023. RESULTS: A total of 32 studies were included, evaluating 30 different transition-to-practice programs with a wide range of intervention components including stress management, clinical education, professional and peer support, and ward rotations. Transition-to-practice programs were often designed without a theoretical foundation. Driving mechanisms behind the programs pertained to psychological, professional, and social development. Contextual factors that activated the mechanisms were enabling conditions for mentors and novice nurses, selection and motivation of novice nurses and organizational culture. CONCLUSIONS: Current transition-to-practice programs primarily focus on the individual and professional development of nurses. However, transition to practice can benefit from a systemic approach that includes development initiatives on the organizational level. REGISTRATION: PROSPERO ID CRD42021268080, August 15, 2021. TWEETABLE ABSTRACT: Context and mechanisms determine successful implementation of transition to practice programs for novice nurses. @transitiontopractice @nurseworkforce.

Lessons learned from the experiences of patients with chronic pelvic pain syndrome (CPP syndrome) with a multidisciplinary consultation: a qualitative study.

INTRODUCTION: Chronic pelvic pain syndrome is a complex multifactorial condition with an increasing prevalence probably due to a rising awareness. Chronic pelvic pain syndrome is pain in the pelvic area and often accompanied with complaints in other organ systems of the lesser pelvis. Patients with chronic pelvic pain syndrome who present at our center are evaluated in a standardized care pathway with an integrated multidisciplinary consultation. The team works in a single center and consists of gynecologists, pain specialists, urologists, a pelvic floor physiotherapist and a psychologist. The aim of this interview study is to evaluate the value of the multidisciplinary consultation from the patient's perspectives. METHODS: In a qualitative study, we evaluated the experiences and perspectives of patients with chronic pelvic pain syndrome concerning the multidisciplinary consultation at the Radboud University Medical Center. Semistructured interviews were conducted with patients with chronic pelvic pain syndrome who attended a multidisciplinary consultation between 2019 and 2022. All interviews were transcribed verbatim, coded and analyzed via ATLAS.ti with the conventional content analysis. RESULTS: Data saturation was reached after seven interviews, followed by three confirmative interviews. In total, 10 patients (22-76 years) participated in the study. Three relevant themes were identified in the interviews: the deleterious effects of pain on overall health, the importance of the design of the multidisciplinary consultation, and the performance of healthcare professionals (knowledge, skills and interaction with patients and colleagues). Participants suggested that although the consultation did not improve their pain experience, there was value in having a comprehensive assessment of their disease. Patients preferred the consultation to occur at the beginning of the care. Additionally, they acknowledged the performance of healthcare providers and having their complaints recognized. However, some participants suggested the need for additional attention to mental health issues during the multidisciplinary consultation. DISCUSSION: Even though patients did not perceive the multidisciplinary consultation to improve their pain experience, they appreciated the sense of recognition by this team. CONCLUSION: A multidisciplinary consultation is of value from the patients' perspective. A suggestion for improvement emerged where the multidisciplinary consultation should occur at the beginning of the patient journey.

Effectiveness of a positive psychology and mindfulness-based app on mental health for parents of children with a neurodevelopmental disorder: study protocol of a pragmatic international randomized controlled trial.

INTRODUCTION: Parents of children with a neurodevelopmental disorder (NDD) experience more stress than parents of typically developing children. In a cocreation process with experts and parents, a low-threshold application that uses exercises based on the principles of positive psychology and mindfulness was developed. This application, called "Adappt," aims at enhancing the ability to adapt of the parents and caregivers of children with NDDs and at supporting their mental health. This protocol describes the evaluation study of the effectiveness of Adappt, its core working mechanisms and user experiences. METHOD: A pragmatic international multicenter randomized controlled trial will compare the effectiveness of Adappt with a (delayed) waitlist control condition. At least 212 parents or primary caregivers of children younger than 18 years diagnosed with or suspected of a NDD will be randomly assigned to the intervention or waitlist control condition. Participants are excluded if they have severe anxiety or depression levels or are in treatment for mental health issues. Measures will be collected online at baseline, post-intervention (1 month after baseline), and 4 and 7 months after baseline. The primary outcome is the improvement in generic sense of ability to adapt as measured with the Generic Sense of Ability to Adapt Scale (GSAAS; (Front Psychol 14:985408, 2023)) at 4-month follow-up. Secondary outcomes are mental well-being, (parental) distress, and client satisfaction with "Adappt." DISCUSSION: Results of this study will contribute to knowledge on the effectiveness of a low-threshold application for parents of children with a NDD in multiple countries. If the application is found to be effective in improving mental health, recommendations will be made for implementation in health care. TRIAL REGISTRATION: This study is registered on clinicaltrials.gov (NCT06248762) on February 8, 2024, and the Open Science Framework ( https://osf.io/5znqv ).

Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families.

PURPOSE: Female CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether CHEK2 c.1100delC is associated with an increased risk for other cancers within these families. METHODS: Including 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10,000 person-years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onward. Attained-age analyses were performed for sites in which significant increased risks were found. Considering the study design, we primarily focused on cancer risk in women. RESULTS: We found significant increased risks of colorectal cancer (CRC; SIR = 1.43, 95% CI = 1.14-1.76; AER = 1.43) and hematological cancers (SIR = 1.32; 95% CI = 1.02-1.67; AER = 0.87). CRC was significantly more frequent from age 45 onward. CONCLUSION: A significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some CHEK2 c.1100delC families might benefit from this surveillance as well; however, further research is needed to determine who may profit from this additional colorectal surveillance.

Biomechanical comparison of bone staple fixation methods with suture material for median sternotomy closure using 3D-printed bone models.

AIM: To compare the biomechanical properties of three different sternal closure techniques in a 3D-printed bone model of a sternum from a 30-kg dog. METHODS: Median sternotomy was performed on a total of 90 three-dimensional (3D) copies of a polycarbonate (PC) model of a sternum, generated from the CT images of the sternum of a 30-kg German Shepherd dog. Three different methods were used to repair the sternotomies: polydioxanone suture (group PDS, n = 30), stainless steel bone staples (group SS, n = 30), and nitinol bone staples (group NS, n = 30). Each repair method was tested by applying tensile force in one of three ways (longitudinally, laterally, or torsionally) resulting in a sample size of n = 10 for each repair method-loading combination. In all experiments, the loads at 1-mm and 2-mm gap formation, failure, and the displacement at the failure point were measured. RESULTS: In lateral distraction and longitudinal shear tests, NS and SS staple repairs required application of significantly greater force than PDS across all displacement criteria (1 and 2 mm). NS exhibited significantly greater failure load than PDS. In torsion tests, NS required significantly greater application of force compared to SS or PDS at all displacement criteria (1 and 2 mm) and exhibited a greater failure load than PDS. In terms of displacement at failure point, PDS suture showed more displacement than SS or NS across all experiments (laterally, longitudinally, torsionally). CONCLUSIONS: In this study, bone staples were mechanically superior to PDS suture in median sternotomy closure using 3D-printed bone model in terms of 1-mm, 2-mm displacement loads, and displacement at failure. NS had a higher failure load than PDS under lateral, longitudinal, and torsional distraction. CLINICAL RELEVANCE: These study results imply that bone staples can be considered as an alternative surgical method for median sternotomy closure in dogs.

Clinical characteristics and management of orbital apex syndrome: a 10-year multicentre experience.

BACKGROUND: Orbital apex syndrome (OAS) is a condition characterised by lesions within the orbital apex, leading to various ophthalmologic symptoms. This study aimed to analyse the clinical characteristics and treatment strategies of OAS with respect to aetiology. METHODS: This retrospective analysis utilised data from 5 medical institutions between 2013 and 2022. Patients who were diagnosed with OAS were initially enrolled, but patients who failed to follow up at least 1 month were excluded. The prevalence of initial ophthalmologic symptoms and visual improvement after treatment was compared according to aetiology. Factors related to visual improvement were analysed. RESULTS: Among 73 enrolled patients, the leading aetiology was tumours, followed by fungal infections and inflammation. Visual impairment and proptosis were prevalent in tumour-related OAS cases. Inflammation-related OAS exhibited a higher likelihood of painful eye movements and ophthalmoplegia. Ptosis was most frequently observed in fungal infection-related OAS. Notably, fungal infections emerged as the sole significant factor negatively impacting vision progression. In inflammation-related OAS, the time interval between symptom onset and the administration of steroids was longer in patients without visual improvement, even though there was no statistically significant difference. CONCLUSIONS: Tumours were the predominant cause of OAS. Visual impairment was a common manifestation in tumour-related OAS, while fungal infections were strongly associated with a poor visual prognosis. The timely administration of steroids might be helpful for improving vision in patients with inflammation-related OAS. However, further studies are needed to enhance understanding and management of OAS.

Platelets Induce Cell Apoptosis of Cardiac Cells via FasL after Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Cell apoptosis in the myocardium plays an important role in ischemia and reperfusion (I/R) injury, leading to cardiac damage and dysfunction. Platelets are major players in hemostasis and play a crucial role in vessel occlusion, inflammation, and cardiac remodeling after I/R. Here, we studied the impact of platelets on cell apoptosis in the myocardium using a close-chest mouse model of AMI. We found caspase-3-positive resident cardiac cells, while leukocytes were negative for caspase-3. Using two different mouse models of thrombocytopenia, we detected a significant reduction in caspase-3 positive cells in the infarct border zone after I/R injury. Further, we identified platelet FasL to induce cell apoptosis via the extrinsic pathway of Fas receptor activation of target cells. Mechanistically, hypoxia triggers platelet adhesion to FasR, suggesting that platelet-induced apoptosis is elevated after I/R. Platelet-specific FasL knock-out mice showed reduced Bax and Bcl2 expression, suggesting that platelets modulate the intrinsic and extrinsic pathways of apoptosis, leading to reduced infarct size after myocardial I/R injury. Thus, a new mechanism for how platelets contribute to tissue homeostasis after AMI was identified that should be validated in patients soon.

Cell-based influenza vaccines: An effective vaccine option for under 60-year-olds.

Aim: Seasonal influenza poses a significant burden of disease, affecting not only older adults but also individuals under the age of 60. It carries a high economic burden, mainly driven by influenza-associated productivity losses in the working population. Conventional egg-based influenza vaccines may have reduced effectiveness due to antigen adaptation in eggs. In contrast, cell-based influenza vaccines are less likely to be affected by such antigen adaptation. This review aims to present real-world data (RWD) comparing the effectiveness of quadrivalent cell-based (QIVc) and egg-based (QIVe) influenza vaccines over three consecutive seasons. Methods: A comprehensive review was conducted, analyzing RWD from retrospective cohort and case-control studies on the relative vaccine effectiveness (rVE) of QIVc versus QIVe during the 2017/18-2019/20 seasons. Results: This study included six retrospective cohort studies and one case-control study, with a combined total of approximately 29 million participants. A cohort study involving people aged ≥4 years during the 2017/18 season showed a statistically significant rVE of QIVc compared to QIVe in preventing influenza-like illness, with a value of 36.2%. QIVc demonstrated statistically significant superiority over QIVe in preventing outpatient and inpatient medical encounters as observed in two cohort studies conducted during the 2018/19 and 2019/20 seasons. The rVE of QIVc compared to QIVe was found to be 7.6% in individuals aged ≥4 years and 9.5% in individuals aged ≥18 years. Three additional cohort studies conducted between 2017/18-2019/20 reported a statistically significant improvement in rVE (5.3-14.4%) of QIVc compared to QIVe in preventing influenza-related hospitalizations and emergency department visits due to influenza in individuals aged 4-64 years. In a case-control study across all three seasons, QIVc showed statistically significantly higher effectiveness compared to QIVe in preventing test-confirmed influenza, with rVEs of 10.0-14.8%. Conclusions: RWD from the 2017/18-2019/20 seasons demonstrated that QIVc is more effective than QIVe in preventing influenza-related outcomes in individuals aged 4-64 years. Preferential use of cell-based influenza vaccines, as opposed to conventional egg-based vaccines, could reduce the burden of influenza-related symptoms on individuals and alleviate the economic impact on the German population under 60 years of age.