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Congenital heart disease (CHD) is the most common congenital anomaly and is an important cause of infant morbidity and mortality. Besides the epigenetic and environmental basis of CHD, genetics plays a central role in CHD pathogenesis. Traditional genetic testing strategies including conventional chromosome analysis, fluorescence in situ hybridization, and Sanger sequencing have largely focused on syndromic CHD or selected CHD phenotypes that are strongly associated with a particular genotype. The landscape of clinical genetic testing in CHD is rapidly evolving due to technical advances in genetic testing, including the identification of copy number variants by chromosomal microarray and nucleotide level alterations/variants by next-generation sequencing (NGS), which are essential to detect genetic causes of CHD and identify associations between genotypes and longitudinal clinical phenotypes. Whole-exome and whole-genome NGS not only reveal pathogenic variants in CHD genes, but also identify non-coding variants that influence the expression of CHD genes. Given the increasing availability and cost-effectiveness of clinical NGS to provide information on the causes of CHD and to detect incidental findings that are clinically actionable, the guidance of genetic counselors or experienced clinicians is essential. The identification of definitive causal CHD variants influences patient care and helps to inform the risk of recurrence, prenatal genetic counseling, and pre-implantation testing for the family of a CHD infant and adults with repaired/palliated CHD. Prenatally, circulating cell-free DNA screening as a non-invasive approach is available as early as 9 weeks of gestation and can screen for the common aneuploidies, which may underlie CHD. In this review, we present past and recent genetic testing in CHD based on our increased understanding of the pathogenesis of CHD along with current challenges with the interpretation of de novo genetic variants. Identification of a genetic diagnosis can help to predict and potentially improve clinical outcomes in CHD patients.

The Karuhan Urang Indigenous Community (AKUR) Cigugur, West Java, is one of the traditional communities that still adheres to the Sunda Wiwitan belief. This community lives side by side with mutual respect for the views of other religions. At the Seren taun ceremony, people from various religions attended and prayed together in Paseban Tri Panca Tunggal. The preservation of Paseban Tri Panca Tunggal is an effort to continue the tradition of the community's ancestors, Prince Sadewa Madrais Alibasa. Ancestral teachings embedded in society are manifested in the form of strong tolerance and a sense of universal brotherhood in the Cigugur Indigenous Community. The study uses a structuralism approach to uncover the structure of settlements consisting of aspects of the form and function of the settlement elements. With syntagmatic analysis, research seeks to look for relations between elements of settlements and reveal the meaning of elements of the settlement system. Cultural identity of the people who uphold the values of humanity and nationality can be a cultural capital for the Cigugur Village development process.

Individuals with schizophrenia or substance use disorder have a substantially increased mortality compared to the general population. Despite a high and probably increasing prevalence of comorbid substance use disorder in people with schizophrenia, the mortality in the comorbid group has been less studied and with contrasting results. We performed a nationwide open cohort study from 2009 to 2015, including all Norwegians aged 20-79 with schizophrenia and/or substance use disorder registered in any specialized health care setting in Norway, a total of 125,744 individuals. There were 12,318 deaths in the cohort, and total, sex-, age- and cause-specific standardized mortality ratios (SMRs) were calculated, comparing the number of deaths in patients with schizophrenia, schizophrenia only, substance use disorder only or a co-occurring diagnosis of schizophrenia and substance use disorder to the number expected if the patients had the age-, sex- and calendar-year specific death rates of the general population. The SMRs were 4.9 (95% CI 4.7-5.1) for all schizophrenia patients, 4.4 (95% CI 4.2-4.6) in patients with schizophrenia without substance use disorder, 6.6 (95% CI 6.5-6.8) in patients with substance use disorder only, and 7.4 (95% CI 7.0-8.2) in patients with both schizophrenia and substance use disorder. The SMRs were elevated in both genders, in all age groups and for all considered causes of death, and most so in the youngest. Approximately 27% of the excess mortality in all patients with schizophrenia was due to the raised mortality in the subgroup with comorbid SUD. The increased mortality in patients with schizophrenia and/or substance use disorder corresponded to more than 10,000 premature deaths, which constituted 84% of all deaths in the cohort. The persistent mortality gap highlights the importance of securing systematic screening and proper access to somatic health care, and a more effective prevention of premature death from external causes in this group.

OBJECTIVE: At temperate latitudes, 1–5% of the population suffer from winter depression; during winter, mood difficulties tend to increase but may be alleviated by bright light therapy. Unlike indoor workers, outdoor workers are exposed to therapeutic levels of sunlight during winter. We hypothesized that outdoor work may protect against mood difficulties and depression. METHOD: We studied this hypothesis among 2910 civil servants from Århus, Denmark, who participated in a survey in January–February 2009. Mental symptoms (N=422) defined a common case category that we broke down into two parts: depression (N=66) and mood difficulties but no depression (N=356). A total of 222 controls were also sampled from the study population. All 644 participants reported the extent of outdoor work. RESULTS: The confounder-adjusted odds ratio (OR) of mood difficulties showed a decreasing trend by increasing hours of outdoor work of borderline statistical significance. The OR was 0.63 [95% confidence interval (95% CI) 0.34–1.18)] for those working outdoors for >2 hours a day. No such effect was suggested for depression. CONCLUSION: Our study is limited by its cross-sectional design and low statistical power but nevertheless suggests that outdoor work during winter may protect against mood difficulties. If this finding holds true it may have significant impact on workers’ health as well as public health in general. Therefore, further studies are recommended.

Abstract TRIM25 is an RNA-binding ubiquitin E3 ligase with central but poorly understood roles in the innate immune response to RNA viruses. The link between TRIM25’s RNA binding and its role in innate immunity has not been established. Thus, we utilized a multitude of biophysical techniques to identify key RNA-binding residues of TRIM25 and developed an RNA-binding deficient mutant (TRIM25-m9). Using iCLIP2 in virus-infected and uninfected cells, we identified TRIM25’s RNA sequence and structure specificity, that it binds specifically to viral RNA, and that the interaction with RNA is critical for its antiviral activity.

In 2020 verscheen de landelijke Kennis- en Onderzoeksagenda Sociaal Werk. In deze agenda wordt de sociale kwaliteit benadering als relevant en bruikbaar gezien voor de doorontwikkeling van het beroep sociaal werk. In dit artikel geven we de kern van deze benadering weer en belichten de potentie voor het sociaal werk. Op basis van de uitkomsten van een literatuurstudie en een online uitvraag laten we zien welke toepassingen van de sociale kwaliteit benadering er in het sociaal werk zijn. Voortbouwend op deze toepassingen bieden we in het laatste deel van het artikel handvatten voor verdere wetenschappelijke onderbouwing en doorontwikkeling van het sociaal werk. Dit doen we aan de hand van de vier kennispijlers van de Kennis- en Onderzoeksagenda: bevorderen van sociale samenhang; bevorderen van inclusie; versterken van het gewone leven; en laten doorklinken van de stem van de burger/inwoner. We laten zien hoe in onderzoek naar sociaal werk de constitutionele, conditionele en normatieve factoren van de sociale kwaliteit benadering kunnen worden gebruikt.

Abstract Remote monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimer’s disease, this is particularly relevant for patients who seek medical advice due to memory problems. Here, we develop a remote digital memory composite (RDMC) score from an unsupervised remote cognitive assessment battery focused on episodic memory and long-term recall and assess its construct validity, retest reliability, and diagnostic accuracy when predicting MCI-grade impairment in a memory clinic sample and healthy controls. A total of 199 participants were recruited from three cohorts and included as healthy controls (n = 97), individuals with subjective cognitive decline (n = 59), or patients with mild cognitive impairment (n = 43). Participants performed cognitive assessments in a fully remote and unsupervised setting via a smartphone app. The derived RDMC score is significantly correlated with the PACC5 score across participants and demonstrates good retest reliability. Diagnostic accuracy for discriminating memory impairment from no impairment is high (cross-validated AUC = 0.83, 95% CI [0.66, 0.99]) with a sensitivity of 0.82 and a specificity of 0.72. Thus, unsupervised remote cognitive assessments implemented in the neotiv digital platform show good discrimination between cognitively impaired and unimpaired individuals, further demonstrating that it is feasible to complement the neuropsychological assessment of episodic memory with unsupervised and remote assessments on mobile devices. This contributes to recent efforts to implement remote assessment of episodic memory for case-finding and monitoring in large research studies and clinical care.

Abstract Background Monoclonal antibodies (biologics) drastically changed severe asthma therapy. Mepolizumab (anti-interleukin (IL) 5), benralizumab (anti-IL5 receptor alpha), and dupilumab (anti-IL4/13) are the most used biologics in this context. While all biologics are efficient individually, the choice of biologic is complicated by insufficient data on their comparative long-term treatment efficacy. Here, we compare the real-life efficacy of these biologics in asthma therapy over 12 months. Methods 280 severe asthma patients treated with mepolizumab (129/280, 46%), benralizumab (83/280, 30%) or dupilumab (68/280, 24%) for one year were analyzed retrospectively. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels as well as responder status measured by the recently published “Biologic Asthma Response Score” (BARS). Results All biologics led to significant improvements in PF, ACT and OCS dose. Only Mepolizumab and Benralizumab significantly decreased the exacerbation rate, while only Mepolizumab and Dupilumab significantly decreased FeNO. Responder rates measured by BARS were high across all groups: roughly half of all patients achieved full response and most of the remainder achieved at least partial responder status. Overall, outcomes were similar between groups after both 6 and 12 months. Conclusions All biologics showed great efficacy in individual parameters and high responder rates measured by BARS without a clinically relevant advantage for any antibody. Response was usually achieved after 6 months and retained at 12 months, emphasizing the utility of early response assessment.

Abstract Background This study explores morphologic changes in the Ahr River, Germany, caused by the high-energy flood in mid-July 2021. This study aims to assess the flood's significance as a morphological driver using the Lateral Mobility Index (LMI), as well as the impact of infrastructure on morphodynamics in terms of the formation of mud deposits and stagnant water pools, considering three focus areas of about 1 to 5 km river length. The three focus areas cover differences in the valley morphology as well as near natural and anthropogenically affected sections. Results The LMI is derived from orthophotos from 1998 to 2022, and based on the surface area of the old and the new channel. It describes the sum of new and abandoned channel area in relation to the previous channel area. For the 2021 high-energy event, an increased LMI suggests an increasing change in river course and morphology. Post-flood, the LMI in focus areas 1 (furthest upstream, LMI of 1.5) and 3 (at the Rhine confluence, LMI of 3.2) surpasses the historic LMI by a factor of about 3. Focus area 3 exhibits the highest activity, while focus area 2 (LMI between 0.25 and 0.70) the lowest. The area of mud deposits and stagnant water pools increased immediately after the flood, especially in focus area 3. Over the following months, initial post-flood mud deposits not only washed away but also rebuilt to some degree later on. Conclusions The LMI enabled to quantitatively identify a rare and significant morphological disruption in the Ahr River’s lateral development in three focus areas, and thus, serves as additional proof that the flood of mid-July 2021 was a high-energy event impacting the local river geomorphology. Infrastructure impacted the formation of mud deposits and stagnant water zones during and after the flood, with additional influence from factors such as driftwood and valley width. The data suggested a phase of resuspension of sediments after the flood, likely due to cleanup and ad hoc river management, highlighting the need for continued river monitoring.

Sand flies (Diptera, Psychodidae) are the principal vectors of Leishmania spp., the causative agents of leishmaniasis, as well as phleboviruses. In the Balkans, the endemicity and spreading of sand fly-borne diseases are evident, particularly in the Republic of Kosovo, a country with a predominantly humid continental climate. To date, understanding the drivers behind the spatial structure and diversity patterns of sand fly communities in humid continental regions remains limited. Therefore, elucidating the geographical and ecological factors contributing to the presence of potential vector species in the country is crucial. We aimed to enhance our understanding of factors influencing sand fly occurrence in cool and wet wintering humid continental areas, which could serve as a model for other countries with similar climatic conditions. Therefore, we assessed the currently known sand fly fauna through detailed environmental analyses, including Voronoi tessellation patterns, entropy calculations, Principal Coordinate and Component Analyses, Hierarchical Clustering, Random Trees, and climatic suitability patterns.Notable differences in the ecological tolerance of the species were detected, and the most important climatic features limiting sand fly presence were wind speed and temperature seasonality. Sand flies were observed to prefer topographical environments with little roughness, and the modelled climatic suitability values indicated that, dominantly, the western plain regions of Kosovo harbour the most diverse sand fly fauna; and are the most threatened by sand fly-borne diseases. Phlebotomus neglectus and P. perfiliewi, both confirmed vectors for L. infantum and phleboviruses, were identified as two main species with vast distribution in Kosovo. Contrary to this, most other present species are relatively sparse and restricted to temperate rather than humid continental regions.Our findings reveal a diverse potential sand fly fauna in Kosovo, indicating the need for tailored strategies to address varying risks across the country's western and eastern regions in relation to leishmaniasis control amidst changing environmental conditions.

Background. Failure to close the abdominal wall after intestinal transplantation (ITx) or multivisceral Tx remains a surgical challenge. An attractive method is the use of nonvascularized rectus fascia (NVRF) in which both layers of the donor abdominal rectus fascia are used as an inlay patch without vascular anastomosis. How this graft integrates over time remains unknown. The study aims to provide a multilevel analysis of the neovascularization and integration process of the NVRF. Methods. Three NVRF-Tx were performed after ITx. Clinical, radiological, histological, and immunological data were analyzed to get insights into the neovascularization and integration process of the NVRF. Moreover, cryogenic contrast-enhanced microfocus computed tomography (microCT) analysis was used for detailed reconstruction of the vasculature in and around the NVRF (3-dimensional histology). Results. Two men (31- and 51-y-old) and 1 woman (49-y-old) underwent 2 multivisceral Tx and 1 combined liver-ITx, respectively. A CT scan showed contrast enhancement around the fascia graft at 5 days post-Tx. At 6 weeks, newly formed blood vessels were visualized around the graft with Doppler ultrasound. Biopsies at 2 weeks post-Tx revealed inflammation around the NVRF and early fibrosis. At 6 months, classical 2-dimensional histological analysis of a biopsy confirmed integration of the fascia graft with strong fibrotic reaction without signs of rejection. A cryogenic contrast-enhanced microCT scan of the same biopsy revealed the presence of microvasculature, enveloping and penetrating the donor fascia. Conclusions. We showed clinical, histological, and microCT evidence of the neovascularization and integration process of the NVRF after Tx.

Purpose: To explore the perception of physical exercise programs for pediatric oncology patients among childhood cancer care professionals. We also aimed at comparing such perceptions between cultures. Healthcare professionals’ endorsement may be essential for initiating and promoting such programs. Methods: An anonymous survey was designed and administered voluntarily to childhood cancer care professionals (including pediatric oncologists, nurses, and physiotherapists) in European, North-African and Arab pediatric oncology centers. Results: Five-hundred-and twenty-eight professionals from 14 sites answered the survey. Most respondents considered physical exercise programs as a suitable therapeutic approach for pediatric cancer patients with a potential positive contribution to survival (81%), wellbeing (82%), quality of life (80%), and self-esteem (75%). 91% of respondents would also support the future introduction of physical exercise programs into standard pediatric oncological care. There was a comparatively higher appreciation of physical exercise programs among European centers compared to North-African / Arab centers. Conclusion: We registered a broad acceptance of physical exercise programs among all European and North-African / Arab childhood cancer care professionals. The positive perception was independent of any pre-existing experience with such programs and seems therefore representative. This finding may encourage the further promotion of physical exercise programs in pediatric oncology.

Astana Gunungjati is a tomb complex for the descendants of the palaces in Cirebon. One of them is the tomb of Sunan Gunungjati, one of The Walisanga and also the King of the Cirebon Sultanate. The purpose of this research was to describe the phenomenon of intangible heritage cultural values from Jeneng-Bekel-Kemit in Astana Gunungjati. Jeneng-Bekel-Kemit is the term used for the caretaker of the tomb. The existence of a caretaker known as kuncen in the Astana Gunungjati room played an important role in the service of tomb pilgrimage tourists. Kuncen at Astana Gunungjati has a unique value system in his work, and values are part of a culture that is an intangible heritage. The research method used a qualitative descriptive method. The method of data collection was carried out by interviewing several kuncen who were met by using Snowball. Field observations were carried out to visually record the space and the activities of the kuncen. The analysis method was carried out using qualitative description. Data was collected and classified. Observations made to the linkage among groups of categories to form a concept. The results of the research show ethical, spiritual, cultural, and esoteric values. The findings can be documented as intangible text attached to the Astana Gunungjati space.

Abstract Background A Meningitis and Encephalitis Surveillance (MERIN) was implemented in 2003 in Lower Saxony, Germany as an alternative to acute flaccid paralyses surveillance, as the latter did not reach WHO sensitivity criteria. The system provides information on circulating enterovirus (EV) serotypes by focussing on patients with suspected aseptic meningitis, encephalitis or acute flaccid paralysis and contributes to the national surveillance in documenting polio free status. MERIN is based on voluntary participation of hospitals. Therefore, our evaluation focusses on acceptability of the system’s objectives and performance, and identifying areas for improvement. Methods To assess acceptability, 32 contributing hospitals were invited to an online-based survey (11/2021 to 01/2022) to rate the MERIN objectives, laboratory’s performance, their workload, modes of processes and communication. Ideas for improvement were collected in open fields. In addition, data completeness and timeliness of laboratory diagnostics were assessed. Results Of 32 hospitals, 21 responded (66% response rate), sending 30 questionnaires, 25 from pediatric and 5 from neurological departments. High levels of satisfaction with the communication (≥ 96%), timeliness (≥ 81%), and distribution of the results (≥ 85%) were reported, 97% of participants judged the required workload as adequate. The median proportion of eligible patients included in MERIN was 75%. Participants gave rapid and reliable diagnostic testing the highest priority (96%), while monitoring of Germany’s polio-free status was rated the lowest (61%). Providing medical reports digitally as well as regular updates about circulating EV serotypes were identified as areas for improvement. Data completeness of selected variables ranged from 78.3 to 99.9%. Median time between sample collection and arrival at laboratory was 2 days [IQR 1–3], EV diagnostics via PCR took one day [IQR 0–6] and EV isolation on cell culture 11 days [IQR 10–13]. Conclusion MERIN is a highly accepted surveillance system. Its quality was enhanced further by addressing the suggested improvements such as regular reports on circulating EV serotypes and facilitating digital access to laboratory results. Our results emphasise the importance of recognizing and considering participants’ motivations and expectations, and addressing their priorities, even if this is not the surveillance system’s main focus. This approach can be applied to surveillance systems of other non-mandatory notifiable diseases.

Abstract Phlebotomine sand flies (Diptera: Phlebotominae) are the principal vectors of Leishmania spp. (Kinetoplastida: Trypanosomatidae). In Central Europe, Phlebotomus mascittii is the predominant species, but largely understudied. To better understand factors driving its current distribution, we infer patterns of genetic diversity by testing for signals of population expansion based on two mitochondrial genes and model current and past climate and habitat suitability for seven post-glacial maximum periods, taking 19 climatic variables into account. Consequently, we elucidate their connections by environmental-geographical network analysis. Most analyzed populations share a main haplotype tracing back to a single glacial maximum refuge area on the Mediterranean coasts of South France, which is supported by network analysis. The rapid range expansion of Ph. mascittii likely started in the early mid-Holocene epoch until today and its spread possibly followed two routes. The first one was through northern France to Germany and then Belgium, and the second across the Ligurian coast through present-day Slovenia to Austria, toward the northern Balkans. Here we present a combined approach to reveal glacial refugia and post-glacial spread of Ph. mascittii and observed discrepancies between the modelled and the current known distribution might reveal yet overlooked populations and potential further spread.

Fibromatous epulis is one of the most common features of the gingival enlargement. This condition results from inflammation of the gingiva, leading to fibrotic overgrowth caused by local or systemic factors. These enlargements increase gingival pocket depth, which may lead to periodontal disease causing functional disturbances in mastication, altered speech, aesthetics, and even psychological problems. A- 42-year-old male patient with gingival fibrotic overgrowth known as fibromatous epulis on proximal teeth in the middle upper front region extended to the palatal and accompanied by slight pain. The clinical appearance of this lesion was firm, slightly soft, and fibrotic, with 6 mm probing depth and bleeding on gingival probing at the proximal of 11 and 21 teeth region. In this case, periodontal surgery to eliminate gingival enlargement was a gingivectomy under local anaesthesia. The fibromatous epulis was entirely eliminated by gingivectomy, also effectively treated the inflammation, facilitated oral prophylaxis procedure, and increased the aesthetics.

Introduction: The ratification of the New Criminal Code actually has an orientation towards strengthening legal pluralism in the field of criminal law. This is evidenced by the adoption of customary criminal law as a recognized law in addition to national criminal law. Purposes of the Research: This study aims to analyze the implications of the formulation of Article 2 of the New Criminal Code concerning the practice of Indonesian criminal law pluralism and the future orientation of the formulation of Article 2 of the New Criminal Code to strengthen the pluralism of Indonesian criminal law. Methods of the Research: This research is a normative legal research that uses a concept and statutory approach. Results of the Research: The study results show that the legal implications of formulating guarantees for the enforceability of laws that live in society affirm the existence of customary criminal law as a living law in society, thereby affirming the essence of legal pluralism. The future orientation of Indonesian criminal law pluralism after the enactment of the New Criminal Code is to maintain harmonious relations between the national legal system and the customary law system and to conduct an inventory of existing customary criminal laws. Customary criminal law that still exists is then regulated specifically in regional regulations in each region so that judges can then use it as a reference in deciding a criminal case that has a legal essence that lives in society.

Preparing for childbirth is crucial because it was a demanding and exhausting experience for unprepared mothers. Confidence in caring for the baby was one of the important indicators of success as a parent. This study aimed to examine the influence of parenting classes on maternal self-efficacy in caring for the baby. The study used a quasi-experimental pre-test and post-test nonequivalent control group design method. The research was conducted at several Midwife Clinical Practices in Bogor City. The sample consisted of 42 pregnant women, with 21 in the intervention group and 21 in the control group. Sampling used non-probability sampling with a purposive sampling technique. The Perceived Maternal Parenting Self-Efficacy (PMP-SE) questionnaire with a likert scale was used to measure the mother's self-efficacy variable in caring for the baby before and after attending the parenting class. The data were analyzed using the Wilcoxon test. The results showed that the mean self-efficacy of mothers in caring for their babies before the intervention was 42.57 (8.577), and after attending the parenting class, it increased to 47.71 (8.344). There was a significant influence of parenting class on mothering self-efficacy in caring for the baby (p=0.015). It is recommended that this model of parenting classes be applied in healthcare settings to educate pregnant women on readiness to become parents, thereby increasing mothers' confidence and ability to take care of their babies after childbirth.

Background: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. Objective: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. Methods: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. Results: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p

Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Abstract System-wide approaches have unveiled an unexpected breadth of the RNA-bound proteomes of cultured cells. Corresponding information regarding RNA-binding proteins (RBPs) of mammalian organs is still missing, largely due to technical challenges. Here, we describe ex vivo enhanced RNA interactome capture (eRIC) to characterize the RNA-bound proteomes of three different mouse organs. The resulting organ atlases encompass more than 1300 RBPs active in brain, kidney or liver. Nearly a quarter (291) of these had formerly not been identified in cultured cells, with more than 100 being metabolic enzymes. Remarkably, RBP activity differs between organs independent of RBP abundance, suggesting organ-specific levels of control. Similarly, we identify systematic differences in RNA binding between animal organs and cultured cells. The pervasive RNA binding of enzymes of intermediary metabolism in organs points to tightly knit connections between gene expression and metabolism, and displays a particular enrichment for enzymes that use nucleotide cofactors. We describe a generically applicable refinement of the eRIC technology and provide an instructive resource of RBPs active in intact mammalian organs, including the brain.

This paper proposes a new Readiness Model, 3D-CUBE, to assess the current state of manufacturing companies in the digital transformation context. Using a systematic literature review with 8-Steps-Search-Flow and a hypothetical-deductive framework (considering maturity as an 'input' enabler and not as an 'output'), the best information of 63 existing models was selected from 486 studies found in 10 databases. The 3D-CUBE was elaborated, with 3 dimensions (X = Organizational , Y = Technological , and Z = Process Maturity), 6 sub-dimensions, and 21 elements, including a scale 0-5 to assess the company readiness level. For the company’s Data Collection, a 3D-CUBE Questionnaire was developed, which provides a radar graph and calculates the company’s score with a readiness vector R=(X,Y,Z). Based on the existing model’s shortcoming, 3D-CUBE is a new contribution to this research stream, to help companies in getting ready for Industry 4.0. .