Ab Initio Uncertainty Quantification of Neutrinoless Double-Beta Decay in

The observation of neutrinoless double-beta (0νßß) decay would offer proof of lepton number violation, demonstrating that neutrinos are Majorana particles, while also helping us understand why there is more matter than antimatter in the Universe. If the decay is driven by the exchange of the three known light neutrinos, a discovery would, in addition, link the observed decay rate to the neutrino mass scale through a theoretical quantity known as the nuclear matrix element (NME). Accurate values of the NMEs for all nuclei considered for use in 0νßß experiments are therefore crucial for designing and interpreting those experiments. Here, we report the first comprehensive ab initio uncertainty quantification of the 0νßß-decay NME, in the key nucleus ^{76}Ge. Our method employs nuclear strong and weak interactions derived within chiral effective field theory and recently developed many-body emulators. Our result, with a conservative treatment of uncertainty, is an NME of 2.60_{-1.36}^{+1.28}, which, together with the best-existing half-life sensitivity and phase-space factor, sets an upper limit for effective neutrino mass of 187_{-62}^{+205} meV. The result is important for designing next-generation germanium detectors aiming to cover the entire inverted hierarchy region of neutrino masses.

The effect of immunosuppressive therapies on the endothelial host response in critically ill COVID-19 patients.

While several effective therapies for critically ill patients with COVID-19 have been identified in large, well-conducted trials, the mechanisms underlying these therapies have not been investigated in depth. Our aim is to investigate the association between various immunosuppressive therapies (corticosteroids, tocilizumab and anakinra) and the change in endothelial host response over time in critically ill COVID-19 patients. We conducted a pre-specified multicenter post-hoc analysis in a Dutch cohort of COVID-19 patients admitted to the ICU between March 2020 and September 2021 due to hypoxemic respiratory failure. A panel of 18 immune response biomarkers in the complement, coagulation and endothelial function domains were measured using ELISA or Luminex. Biomarkers were measured on day 0-1, day 2-4 and day 6-8 after start of COVID-19 treatment. Patients were categorized into four treatment groups: no immunomodulatory treatment, corticosteroids, anakinra plus corticosteroids, or tocilizumab plus corticosteroids. The association between treatment group and the change in concentrations of biomarkers was estimated with linear mixed-effects models, using no immunomodulatory treatment as reference group. 109 patients with a median age of 62 years [IQR 54-70] of whom 72% (n = 78) was male, were included in this analysis. Both anakinra plus corticosteroids (n = 22) and tocilizumab plus corticosteroids (n = 38) were associated with an increase in angiopoietin-1 compared to no immune modulator (n = 23) (beta of 0.033 [0.002-0.064] and 0.041 [0.013-0.070] per day, respectively). These treatments, as well as corticosteroids alone (n = 26), were further associated with a decrease in the ratio of angiopoietin-2/angiopoietin-1 (beta of 0.071 [0.034-0.107], 0.060 [0.030-0.091] and 0.043 [0.001-0.085] per day, respectively). Anakinra plus corticosteroids and tocilizumab plus corticosteroids were associated with a decrease in concentrations of complement complex 5b-9 compared to no immunomodulatory treatment (0.038 [0.006-0.071] and 0.023 [0.000-0.047], respectively). Currently established treatments for critically ill COVID-19 patients are associated with a change in biomarkers of the angiopoietin and complement pathways, possibly indicating a role for stability of the endothelium. These results increase the understanding of the mechanisms of interventions and are possibly useful for stratification of patients with other inflammatory conditions which may potentially benefit from these treatments.

Advances in rectal cancer: Real-world evidence suggests limited gains in prognosis for elderly patients.

BACKGROUND: Rectal cancer treatment has improved considerably due to the introduction of total meso-rectal excision, radio-chemotherapy, and high-resolution imaging. The aim of this observational cohort study was to quantify the effectiveness of these advances using high-quality data from a representative cohort of patients. METHODS: 20 281 non-metastasized cases retrieved from the Munich Cancer Registry database were divided into three time periods corresponding to before (1988-1997), partial (1998-2007), and full implementation (2008-2019) of clinical advances. Early-onset (<50 yrs.), middle-aged, elderly patient subgroups (> 70 yrs.) were compared. The overall effectiveness of evidence-based guideline adherence was also examined. RESULTS: Median survival improved by 1.5 yrs. from the first to the last time period. Relative survival increased from 74.9% (5-yr 95%CI[73.3 - 76.6]) to 79.2% (95%CI[77.8 - 80.5]). The incidence of locoregional recurrences was reduced dramatically by more than half (5-yr 17.7% (95%CI[16.5 - 18.8]); 6.7% (95%CI[6.1 - 7.3])). Gains in 5-yr relative survival were limited to early-onset and middle-aged patients with no significant improvement seen in elderly patients (Female 68.6% [63.9 - 73.3] to 67.6% [64.0 - 71.2]; Male 71.7% [65.9 - 77.4] to 74.0% [70.8 - 77.2]). CONCLUSIONS: Real-world evidence suggests that recent treatment advances have lead to an increase in prognosis for rectal cancer patients. However, more effort should be made to improve the implementation of new developments in elderly patients. Especially considering, that these cases represent a growing majority of diagnosed patients.

Neurophysiology, Neuropsychology, and Epilepsy, in 2022: Hills We Have Climbed and Hills Ahead. Neurophysiology in epilepsy.

Since the discovery of the human electroencephalogram (EEG), neurophysiology techniques have become indispensable tools in our armamentarium to localize epileptic seizures. New signal analysis techniques and the prospects of artificial intelligence and big data will offer unprecedented opportunities to further advance the field in the near future, ultimately resulting in improved quality of life for many patients with drug-resistant epilepsy. This article summarizes selected presentations from Day 1 of the two-day symposium "Neurophysiology, Neuropsychology, Epilepsy, 2022: Hills We Have Climbed and the Hills Ahead". Day 1 was dedicated to highlighting and honoring the work of Dr. Jean Gotman, a pioneer in EEG, intracranial EEG, simultaneous EEG/ functional magnetic resonance imaging, and signal analysis of epilepsy. The program focused on two main research directions of Dr. Gotman, and was dedicated to "High-frequency oscillations, a new biomarker of epilepsy" and "Probing the epileptic focus from inside and outside". All talks were presented by colleagues and former trainees of Dr. Gotman. The extended summaries provide an overview of historical and current work in the neurophysiology of epilepsy with emphasis on novel EEG biomarkers of epilepsy and source imaging and concluded with an outlook on the future of epilepsy research, and what is needed to bring the field to the next level.

A systematic review of axillary nodal irradiation for the management of the axilla in patients with early-stage breast cancer.

BACKGROUND: Given numerous publications and clinical trials regarding axillary management in breast cancer, we sought to summarize this complex literature to help clarify this field for clinicians. This systematic review focuses on the role of irradiation of the axillary nodes (locoregional nodal irradiation [LRNI]) in the management of the axilla in patients with early-stage breast cancer in various clinical settings. METHODS: We searched MEDLINE and EMBASE databases, the Cochrane library, the proceedings of the ASCO, the ASTRO, the ESMO, the ESTRO, and the San Antonio Breast Cancer Symposium (2016-2019) meetings. The quality of the studies was assessed with design-specific tools. The study was registered in PROSPERO. RESULTS: We included one systematic review, one individual patient data (IPD) meta-analysis, and five randomized controlled trials (RCTs). After axillary lymph node dissection (ALND), LRNI resulted in small benefits in breast cancer specific mortality, locoregional recurrence, and distant metastases-free survival but not overall survival. After a positive sentinel node biopsy (SLNB), LRNI may provide equivalent locoregional control and disease-free survival (DFS) compared to ALND with a lower risk of lymphedema. No randomized data is available for the neoadjuvant setting. CONCLUSIONS: The summary of the role of radiation, is relevant to radiation oncologists for choosing the correct cohort of patient requiring LRNI and to surgeons making clinical decisions regarding the timing and type of breast reconstruction offered to patients.

Public Opinion Leadership in Nursing Practice: A Rogerian Concept Analysis.

In the Dutch nursing context, work remains in strengthening the voice of nurses serving as frontline health care providers and board members alike. Conceptual clarity of Public Opinion Leadership (POL) in nursing practice is needed to provide attributes, antecedents and consequences for nurses and nurse leaders so they can contribute in the public debate and policy making processes. Using Rodgers' method of evolutionary concept analysis and the key words "POL," "lobbying" and "public affairs," we searched PubMed (including MEDLINE), CINAHL, PsycINFO and Cochrane Library for articles written in English, published between January 1999 and May 2020, which resulted in a final selection of seven studies. In addition, transcripts of an expert panel discussion regarding POL were analyzed. Attributes of POL are credibility, accessibility, altruism, dynamic networking and sense of systemness. Antecedents are a clinical background, authentic authority, policy and political awareness and strategic skills. The main consequences of POL entail influencing those who are involved in policy making processes, a new generation of public opinion leaders, and the raising of bottom-up political leaders. POL is a relatively new concept for nursing, with increasing interest given the need to ensure quality of care by increasing the use of evidence in clinical practice. POL in nursing practice is defined as the action of influencing public debate regarding policy making processes by maintaining dynamic (social) networks, having a high sense of systemness, and being (clinically) credible, altruistic and accessible to peers and a wide variety of stakeholders.

LIN28 promotes tumorigenesis in colorectal cancer but is not associated with metastatic spread.

BACKGROUND: Tumor stem cells play a role in metastatic spread in colorectal cancer (CRC). The oncogene LIN28A/B, a prognostic marker in CRC, is involved in tumorigenesis and maintains stem cell function. Therefore, it was the aim of the present study to clarify whether LIN28A/B is involved in metastatic spread in CRC. METHODS: Expression of LIN28A/B was analyzed in patients with colon adenocarcinoma in a matched case-control study comparing patients with corresponding liver metastases (n = 42) and patients without hepatic spread within five years (n = 42) by applying immunohistochemistry. Further, LIN28A/B expression was correlated with stem cell associated markers (SOX2, CD133). RESULTS: LIN28A and B expression significantly correlated with SOX2 expression (p = .02, and p = .04 respectively) but not with CD133 expression. This correlation between LIN28 A/B and SOX2 was not reflected in differences in hepatic spread. In this respect, there was no significant association between LIN28A/B expression and liver metastases. CONCLUSION: LIN28A/B might be involved in tumor initiation and progression in CRC but is not associated with hepatic spread.

Outcome of breast cancer patients with low hormone receptor positivity: analysis of a 15-year population-based cohort.

BACKGROUND: Guideline recommendations for the treatment of breast cancer with low hormone receptor (HR) expression (1%-9%) are ambiguous and several studies showed more similarities with HR-negative tumors than with HR strongly positive tumors (≥10%). We used a population-based 15-year cohort to compare patient characteristics and outcome of HR low positive tumors with HR-negative and HR strongly positive tumors, respectively. PATIENTS AND METHODS: A total of 38  560 women diagnosed with early invasive breast cancer between 2004 and 2018 within the scope of the Munich Cancer Registry with 4.9 million inhabitants were included. Descriptive analyses of prognostic factors, treatment, and outcome analyses using the Kaplan-Meier method; cumulative incidence in consideration of competing risks; and multivariate analyses (Cox regression and Fine-Gray model) were conducted. Endpoints were time to local recurrence (TTLR), time to lymph node recurrence (TTLNR), time to metastasis (TTM), overall survival (OS), and relative survival (RS). RESULTS: A total of 861 patients (2%) had HR low positive, 4862 (13%) HR-negative, and 32  837 (85%) HR strongly positive tumors. Within the HER2-negative cohort (n = 33  366), survival of HR low positive tumors was significantly worse than that of HR strongly positive tumors [OS hazard ratio 0.66 (95% confidence interval 0.55-0.78)], whereas between HR low positive and HR-negative tumors no significant survival difference could be detected [OS hazard ratio 0.93 (95% confidence interval 0.78-1.11)]. TTLR, TTLNR, and TTM showed similar results. By contrast, within the HER2-positive cohort (n = 5194), no statistically significant differences between the three HR groups could be detected in multivariate analyses. CONCLUSION: Current definitions for HR positivity and its clinical relevance should be reconsidered. Patients with HR low positive/HER2-negative tumors could be regarded and treated similar to patients with triple-negative tumors.

Coupled-Cluster Calculations of Neutrinoless Double-ß Decay in

We use coupled-cluster theory and nuclear interactions from chiral effective field theory to compute the nuclear matrix element for the neutrinoless double-ß decay of ^{48}Ca. Benchmarks with the no-core shell model in several light nuclei inform us about the accuracy of our approach. For ^{48}Ca we find a relatively small matrix element. We also compute the nuclear matrix element for the two-neutrino double-ß decay of ^{48}Ca with a quenching factor deduced from two-body currents in recent ab initio calculation of the Ikeda sum rule in ^{48}Ca [Gysbers et al., Nat. Phys. 15, 428 (2019)NPAHAX1745-247310.1038/s41567-019-0450-7].

Biomarker alterations associated with distinct patterns of metastatic spread in colorectal cancer.

Metastatic spread is the most important life-threatening feature of colorectal cancer and is supposed to be mainly driven by alterations in different carcinogenic pathways. The present study compared mutation and expression profiles of distinctive biomarkers in colorectal cancer patients with different clinical metastatic patterns. As for a case-control study, patients were matched according to T category, grading and primary tumour site. Overall, 246 patients with either exclusive lung metastasis (N = 82), exclusive liver metastasis (N = 82) or non-metastatic colorectal cancer (N = 82) were identified. Paraffin-embedded specimens were examined for mutations in the RAS and RAF genes and for the expression of ß-catenin and CD133. Clinical endpoints were presence or absence of distant metastasis, formation of metastasis in lungs versus the liver and survival. MAPK pathway mutations in either the KRAS, NRAS or BRAF gene were associated with the development of lung metastasis (63.4%) compared to the control group (47.6%; p = 0.04). MAPK pathway alterations plus high ß-catenin expression were associated with metastasis to the lungs but not to the liver (28.0% vs. 13.4%; p = 0.02). High CD133 expression correlated with the development of liver metastasis compared to the control group (30.5% vs. 14.6%; p = 0.02). This data indicates that different patterns of distant spread are associated with specific biomarker alterations and may represent different molecular subtypes of colorectal cancer. However, underlying mechanisms of metastasis formation in different anatomic sites remains unclear. Since knowledge of the anticipated site of distant spread would substantially impact clinical management, further research is needed to identify solid biomarkers for different metastatic patterns.

Pipkin type IV femoral head fractures: a case series and review of literature.

INTRODUCTION: Femoral head fractures with associated acetabular fractures are uncommon injuries usually resulting from high-energy mechanisms such as motor vehicle collisions. Outcomes of Pipkin type IV fractures have been historically poor, with high rates of osteonecrosis, post-traumatic arthritis, and heterotopic ossification. The objective of this study was to define the outcomes of operatively treated Pipkin type IV fractures In addition, we reviewed the available literature of this uncommon injury pattern. METHODS: A retrospective chart review at a single level 1 trauma center from 2007 to 2016 identified 10 patients with Pipkin IV femoral head fractures. Demographic information, fracture type, associated injuries, operative details, and complications were evaluated. Clinical and radiological outcomes were assessed at latest follow-up including conversion to total hip arthroplasty. RESULTS: Six of the seven patients were treated with open reduction and internal fixation of the femoral head fracture and acetabular fracture through a Kocher-Langenbeck approach aided by a trochanteric flip and one had fragment excision. Six patients (87.5%) developed post-traumatic arthritis. Four (57.1%) later underwent conversion to total hip arthroplasty (THA) a mean of 20.5 months after index procedure. CONCLUSION: Our study shows a rate of osteonecrosis and osteoarthritis that is even higher than the previously reported studies. The former may relate to longer-term follow-up and the latter possibly due to associated comminuted posterior wall fracture.

Gamow-Teller Strength in

We develop a fully self-consistent subtracted second random-phase approximation for charge-exchange processes with Skyrme energy-density functionals. As a first application, we study Gamow-Teller excitations in the doubly magic nucleus ^{48}Ca, the lightest double-ß emitter that could be used in an experiment, and in ^{78}Ni, the single-beta-decay rate of which is known. The amount of Gamow-Teller strength below 20 or 30 MeV is considerably smaller than in other energy-density-functional calculations and agrees better with experiment in ^{48}Ca, as does the beta-decay rate in ^{78}Ni. These important results, obtained without ad hoc quenching factors, are due to the presence of two-particle-two-hole configurations. Their density progressively increases with excitation energy, leading to a long high-energy tail in the spectrum, a fact that may have implications for the computation of nuclear matrix elements for neutrinoless double-ß decay in the same framework.

Ab Initio Treatment of Collective Correlations and the Neutrinoless Double Beta Decay of

Working with Hamiltonians from chiral effective field theory, we develop a novel framework for describing arbitrary deformed medium-mass nuclei by combining the in-medium similarity renormalization group with the generator coordinate method. The approach leverages the ability of the first method to capture dynamic correlations and the second to include collective correlations without violating symmetries. We use our scheme to compute the matrix element that governs the neutrinoless double beta decay of ^{48}Ca to ^{48}Ti, and find it to have the value 0.61, near or below the predictions of most phenomenological methods. The result opens the door to ab initio calculations of the matrix elements for the decay of heavier nuclei such as ^{76}Ge, ^{130}Te, and ^{136}Xe.

Sexual cues alter working memory performance and brain processing in men with compulsive sexual behavior.

Pornography has been repeatedly at the centre of public attention and has been controversially discussed for a long time. However, little is known about the connection between pornographic stimuli and individual (neuronal) processing of attention and memory. Here, the impact and neural underpinnings of pornographic pictures on working memory processes in a sample of subjects with compulsive sexual behaviour was investigated. Therefore, whilst using functional magnetic resonance imaging (fMRI), a letter n-back task with neutral or pornographic pictures in the background was employed in 38 patients and 31 healthy controls. On the behavioural level, patients were slowed down by pornographic material depending on their pornography consumption in the last week, which was reflected by a higher activation in the lingual gyrus. In addition, the lingual gyrus showed a higher functional connectivity to the insula during processing of pornographic stimuli in the patient group. In contrast, healthy subjects showed faster responses when confronted with pornographic pictures only with high cognitive load. Also, patients showed a better memory for pornographic pictures in a surprise recognition task compared to controls, speaking for a higher relevance of pornographic material in the patient group. These findings are in line with the incentive salience theory of addiction, especially the higher functional connectivity to the salience network with the insula as a key hub and the higher lingual activity during processing of pornographic pictures depending on recent pornography consumption.

Lymph node dissection in endometrial cancer and clinical outcome: A population-based study in 5546 patients.

BACKGROUND: According to current treatment guidelines, comprehensive surgical staging procedures in endometrial cancer confined to the uterus depend on uterine risk factors: a systematic lymph node dissection (LND) is recommended in high risk patients and should be omitted in low risk patients. Its role in intermediate and high intermediate risk patients is inconclusive. The aim of this analysis was to review the implementation of this risk-adopted strategy. MATERIALS AND METHODS: Data were provided by the population-based Munich Cancer Registry. Patients with endometrial cancer diagnosed between 1998 and 2016 were included. RESULTS: Of 5446 eligible patients, 58.5%, 30.1% and 11.4% belonged to the low risk, intermediate/high-intermediate and high risk group, respectively. Lymph node dissection was performed in 20.2%, 53.0% and 63.7% within these groups. Lymph node involvement was diagnosed in 1.7%, 9.6% and 19.3%, respectively. Within these risk groups, there was no significant difference in the time to local recurrence, lymph node recurrence or distant metastases between patients with and without LND. After adjusting for age and comorbidity-status, no significant difference in overall survival was found. CONCLUSIONS: The application of a risk-adopted management of LND in early endometrial cancer in real-life is associated with a high rate of surgical under- and overtreatment. Corresponding survival data do not show a significant benefit of a systematic lymph node dissection. In order to improve the management and outcome of early endometrial cancer in the future, prospective trials, new surgical concepts and prognostic markers will be primary and necessary.

Critical comparison of methods for fault diagnosis in metabolomics data.

Platforms like metabolomics provide an unprecedented view on the chemical versatility in biomedical samples. Many diseases reflect themselves as perturbations in specific metabolite combinations. Multivariate analyses are essential to detect such combinations and associate them to specific diseases. For this, usually targeted discriminations of samples associated to a specific disease from non-diseased control samples are used. Such targeted data interpretation may not respect the heterogeneity of metabolic responses, both between diseases and within diseases. Here we show that multivariate methods that find any set of perturbed metabolites in a single patient, may be employed in combination with data collected with a single metabolomics technology to simultaneously investigate a large array of diseases. Several such untargeted data analysis approaches have been already proposed in other fields to find both expected and unexpected perturbations, e.g. in Statistical Process Control. We have critically compared several of these approaches for their sensitivity and their correct identification of the specifically perturbed metabolites. Also a new approach is introduced for this purpose. The newly introduced Sparse Mean approach, which we find here as most sensitive and best able to identify the specifically perturbed metabolites, turns metabolomics into an untargeted diagnostic platform. Aside from metabolomics, the proposed approach may greatly benefit fault diagnosis with untargeted analyses in many other fields, such as Industrial Process Control, food Adulteration Detection, and Intrusion Detection.

The effects of floor space and nest box access on the physiology and behavior of caged laying hens.

Confinement housing appears to be at the forefront of concern about laying hen welfare. This experiment examined the effects of floor space during rearing (315 or 945 cm2/bird) and adulthood (542 or 1648 cm2/bird) and access to a nest box on the welfare of caged laying hens. Measurements of the normality of biological functioning, such as plasma, egg albumen and yolk and fecal corticosterone concentrations, and heterophil to lymphocyte ratios, behavioral time budgets, mortality and efficiency of productivity, and measurement of hen preferences, such as choice behavior in Y maze tests, were used to assess hen welfare. There were no effects of treatment on physiological measurements. Hens given less space during adulthood spent less time mobile, inedible pecking, drinking, and preening and spent more time resting and feed pecking and sitting (P < 0.05). Hens with access to a nest box spent more time resting (P = 0.046) and less time sham dust bathing (P = 0.044) than hens without access to a nest box. There were no effects of space allowance on choice behavior for space or a nest box over food; however, hens with access to a nest box chose the nest box over food more than hens without access to a nest box (P = 0.0053). The present experiment provides no convincing evidence that either reducing space allowance in adulthood from 1648 to 542 cm2/bird or eliminating access to a nest box results in disruption of biological function. Less space and no access to a nest box did not increase the choice for more space or a nest box, respectively, over food in the preference tests. However, reduced floor space reduced behavioral freedom and denying access to a nest box eliminated the opportunity for the motivated behavior of laying their eggs in a discrete enclosed nest box, both of which presumably provide hens with the opportunity for positive affective experiences.

Observation of the Self-Modulation Instability via Time-Resolved Measurements.

Self-modulation of an electron beam in a plasma has been observed. The propagation of a long (several plasma wavelengths) electron bunch in an overdense plasma resulted in the production of multiple bunches via the self-modulation instability. Using a combination of a radio-frequency deflector and a dipole spectrometer, the time and energy structure of the self-modulated beam was measured. The longitudinal phase space measurement showed the modulation of a long electron bunch into three bunches with an approximately 200 keV/c amplitude momentum modulation. Demonstrating this effect is a breakthrough for proton-driven plasma accelerator schemes aiming to utilize the same physical effect.

The resurgence of botulinum toxin injection for strabismus in children.

PURPOSE OF REVIEW: The present review discusses recent advances in the use of botulinum toxin for the management of strabismus in children. RECENT FINDINGS: Botulinum toxin injection produces similar results compared to surgery for certain subtypes of strabismus, especially acute onset esotropia. It may be more effective in many subtypes of esotropia where surgery has been less reliable, including partially accommodative esotropia, esotropia associated with cerebral palsy, and thyroid eye disease. SUMMARY: Small retrospective studies have demonstrated the efficacy of botulinum toxin in the treatment of many types of pediatric strabismus, providing some guidance for clinicians to determine which patients would benefit most from this intervention. Although administration of botulinum toxin is generally accepted as a reasonable option in select cases, many strabismus surgeons have not fully embraced the treatment, in part because of perceived disadvantages compared to surgery and difficulty in identifying subsets with the highest potential for therapeutic success. A recent study compared the administration of botulinum toxin in children with acute-onset esotropia to surgical correction and found botulinum toxin had a statistically equal success rate, but with the advantage of significantly less time under general anesthesia. In addition, botulinum toxin has been recently tried in patients with partially accommodative esotropia, esotropia associated with cerebral palsy, cyclic esotropia, and in patients with thyroid eye disease. The present review will discuss current clinical recommendations based on recent studies on the use of botulinum toxin in children with strabismus.