Patient preferences in genetic newborn screening for rare diseases: study protocol.

INTRODUCTION: Rare diseases (RDs) collectively impact over 30 million people in Europe. Most individual conditions have a low prevalence which has resulted in a lack of research and expertise in this field, especially regarding genetic newborn screening (gNBS). There is increasing recognition of the importance of incorporating patients' needs and general public perspectives into the shared decision-making process regarding gNBS. This study is part of the Innovative Medicine Initiative project Screen4Care which aims at shortening the diagnostic journey for RDs by accelerating diagnosis for patients living with RDs through gNBS and the use of digital technologies, such as artificial intelligence and machine learning. Our objective will be to assess expecting parent's perspectives, attitudes and preferences regarding gNBS for RDs in Italy and Germany. METHODS AND ANALYSIS: A mixed method approach will assess perspectives, attitudes and preferences of (1) expecting parents seeking genetic consultation and (2) 'healthy' expecting parents from the general population in two countries (Germany and Italy). Focus groups and interviews using the nominal group technique and ranking exercises will be performed (qualitative phase). The results will inform the treatment of attributes to be assessed via a survey and a discrete choice experiment (DCE). The total recruitment sample will be 2084 participants (approximatively 1000 participants in each country for the online survey). A combination of thematic qualitative and logit-based quantitative approaches will be used to analyse the results of the study. ETHICS AND DISSEMINATION: This study has been approved by the Erlangen University Ethics Committee (22-246_1-B), the Freiburg University Ethics Committee (23-1005 S1-AV) and clinical centres in Italy (University of FerraraCE: 357/2023/Oss/AOUFe and Hospedale Bambino Gesu: No.2997 of 2 November 2023, Prot. No. _902) and approved for data storage and handling at the Uppsala University (2022-05806-01). The dissemination of the results will be ensured via scientific journal publication (open access).

A comparative ethical analysis of the Egyptian clinical research law.

BACKGROUND: In this study, we examined the ethical implications of Egypt's new clinical trial law, employing the ethical framework proposed by Emanuel et al. and comparing it to various national and supranational laws. This analysis is crucial as Egypt, considered a high-growth pharmaceutical market, has become an attractive location for clinical trials, offering insights into the ethical implementation of bioethical regulations in a large population country with a robust healthcare infrastructure and predominantly treatment-naïve patients. METHODS: We conducted a comparative analysis of Egyptian law with regulations from Sweden and France, including the EU Clinical Trials Regulation, considering ethical human subject research criteria, and used a directed approach to qualitative content analysis to examine the laws and regulations. This study involved extensive peer scrutiny, frequent debriefing sessions, and collaboration with legal experts with relevant international legal expertise to ensure rigorous analysis and interpretation of the laws. RESULTS: On the rating of the seven different principles (social and scientific values, scientific validity, fair selection of participants, risk-benefit ratio, independent review, informed consent and respect for participants) Egypt, France, and EU regulations had comparable scores. Specific principles (Social Value, Scientific Value, and Fair selection of participants) were challenging to directly identify due to certain regulations embodying 'implicit' principles more than explicitly stated ones. CONCLUSION: The analysis underscores Egypt's alignment with internationally recognized ethical principles, as outlined by Emanuel et al., through its comparison with French, Swedish, and EU regulations, emphasizing the critical need for Egypt to continuously refine its ethical regulations to safeguard participant protection and research integrity. Key issues identified include the necessity to clarify and standardize the concept of social value in research, alongside concerns regarding the expertise and impartiality of ethical review boards, pointing towards a broader agenda for enhancing research ethics in Egypt and beyond.

m6A RNA methylation orchestrates transcriptional dormancy during paused pluripotency.

Embryos across metazoan lineages can enter reversible states of developmental pausing, or diapause, in response to adverse environmental conditions. The molecular mechanisms that underlie this remarkable dormant state remain largely unknown. Here we show that N6-methyladenosine (m6A) RNA methylation by Mettl3 is required for developmental pausing in mouse blastocysts and embryonic stem (ES) cells. Mettl3 enforces transcriptional dormancy through two interconnected mechanisms: (1) it promotes global mRNA destabilization and (2) it suppresses global nascent transcription by destabilizing the mRNA of the transcriptional amplifier and oncogene N-Myc, which we identify as a crucial anti-pausing factor. Knockdown of N-Myc rescues pausing in Mettl3-/- ES cells, and forced demethylation and stabilization of Mycn mRNA in paused wild-type ES cells largely recapitulates the transcriptional defects of Mettl3-/- ES cells. These findings uncover Mettl3 as a key orchestrator of the crosstalk between transcriptomic and epitranscriptomic regulation during developmental pausing, with implications for dormancy in adult stem cells and cancer.

Psychiatric and non-psychiatric population vulnerabilities in time of a crisis: the unsuspected aggression factor.

OBJECTIVES: In March 2020, France faced a health crisis due to the COVID-19 outbreak that, like previous infectious disease crises, involved high psychological and emotional stress, a series of factors that influenced the ongoing mental health crisis. METHODS: We recruited 384 respondents to complete an online questionnaire during the second month of isolation: 176 psychotherapy recipients (68 were currently attending psychiatric care) and 208 healthy controls. We measured demographic characteristics, impulsivity, aggression, hopelessness, suicidal risk, and the global level of anxiety and depression in order to estimate potential discrepancies in clinical measures across these populations. RESULTS: Our results indicate that the group currently undergoing psychiatric care was prone to loneliness and social isolation. Regarding clinical and nonclinical population, there were differences in suicidal risk, depression, anxiety, and hopelessness but mainly in aggression. Regression analysis also demonstrated that aggression surprisingly influenced anxiety levels. Patients undergoing therapy compared with patients who were not displayed differences only in suicidal risk, anxiety, and hopelessness, with those undergoing therapy having higher scores. The outpatient group undergoing therapy had a significantly lower level of impulsivity. Moreover, the regression to predict anxiety and depression levels from correlated factors highlighted the potentially heightened role of aggression in predicting anxiety in the clinical group. CONCLUSION: New research into stress reactions should assess other clinical signals, such as aggression, and examine preventive mental health interventions in times of crisis.

Using values in cognitive and behavioral therapy: A bridge back to philosophy.

Ancient therapeutic practices have influenced the development of cognitive behavioral therapy (CBT) theories such as Albert Ellis's rational emotive behavior therapy and Aaron Beck's cognitive therapy. By drawing inspiration from Socratic questioning, the importance of philosophy in evidence-based practices in human mental health can be acknowledged. Stoicism has also informed CBT, notably its emphasis on establishing psychological distance from emotions. Cognition and emotion are two aspects of mental processes, and irrational demands are processed through rational deliberation. Using mental imaging techniques and acceptance strategies (to accept oneself and the world as imperfect), avoiding catastrophic interpretations and acknowledging emotions are also included among such practices. METHODS: We will explore the use of values across CBT, acceptance and commitment therapy (ACT), and radically open dialectical behavioral therapy (RO DBT) to clarify their use of values. RESULTS: In this framework, values are conceptualized as life-orienting principles and are now widely used across CBTs, such as acceptance and commitment therapy and radically open dialectical behavioral therapy. In recent years, the development of CBT has involved a renewed relationship with philosophy through the use of values, interest in dialectics and development of self-questioning practices reminiscent of classical Socratic principles. This movement from applied clinical psychology toward philosophical skills has also encouraged the recent emergence of philosophical health considerations. The opposition between psychological and philosophical health can be questioned, and the fundamental issue of philosophical skills implemented in psychiatric treatment (and not solely as practices of enhancement for the sane) needs to be considered.

Metacognition and insight dynamics exploration in borderline personality disorder: Exploring the underlying dynamics.

Metacognition and Insight are related to hard-to-treat disorders and among them is Borderline Personality Disorder (BPD). We recruited 190 BPD patients and measured Insight, Metacognition, Impulsivity, and BPD traits. Results showed BPD's significant links with Insight and Metacognition. Metacognition significantly correlated with two Impulsivity dimensions, whereas Insight significantly correlated with most of them. Regressions analysis revealed a significant relationship between Insight and Metacognition on Impulsivity and Borderline traits. Mediation analysis proved the indirect effect of Metacognition/Insight on Borderline traits through Impulsivity at a significative level. Both seem relevant for research and therapeutic application in BPD following different dynamics even if the limitation of our study stands in its gender ratio and possible comorbidity issues. Urgency appears as a critical factor to assess, notably with Positive emotion-based impulsivity.

Metacognition vulnerabilities in time of crisis: Who to protect from suicidal risk?

INTRODUCTION: During stressful events, we are all trying to cope. We may not be equal depending on our emotional, psychological, and mental states. During the COVID-19 pandemic, we could try to avoid negative information processing and anxiogenics content to prevent unhealthy thinking processes. One of the processes we can observe regarding our way of thinking and its impact on our psychological well-being is Metacognition. METHODS: We recruited 104 outpatients in 2018. In 2020, during the pandemic, we recruited 216 outpatients and 176 healthy controls. We assessed their level of metacognition with the MCQ30 scale together with Suicidal risk and Hopelessness. RESULTS: All three groups showed significant differences, with the nonclinical sample having higher scores in MCQ30. Regression revealed the different profiles where Hopelessness was the only predictor for the clinical sample, whereas metacognition was an adjunctive predictor of suicidal risk for the nonclinical sample. CONCLUSION: Our results showed that the COVID-19 crisis influenced metacognitive levels for the nonclinical sample but not for the clinical population. Moreover, Hopelessness predicted suicide risk for both populations, but Metacognition was also a predictive factor for the nonclinical sample. We conclude with the possible impact of preventive measures based on Metacognitive work that can be created out of these results.

Just try it: Preliminary results of a six-month therapy for borderline personality disorder.

Borderline Personality Disorder (BPD) is labeled as a personality disorder with impulsivity issues regarding relationships, risky behavior, and emotional dysregulation. This personality disorder is still considered to be hard-to-treat condition even though responses to treatment have improved significantly. In this field, Dialectical Behavioral Therapy is recognized as one of the most efficient therapeutical approaches, and some versions adapted from this gold-standard treatment proved their effectiveness in clinical settings. We tested the 6-month cognitive behavioral therapy (CBT) protocol ECCCLORE, composed of three modules, respectively, working on emotional regulation, distress tolerance, and relationships-in a French context to compare its effectiveness to Treatment As Usual. We recruited 56 patients with a BPD diagnosis in a day-care unit, 34 receiving ECCCLORE and 22 receiving TAU. We assessed BPD traits, impulsivity, aggressiveness, suicidal risk, and hopelessness. Our results revealed the effectiveness of the 6-month ECCCLORE protocol to decrease BPD symptoms and associated clinical dimensions. We also noted the persistence of its effect after a 1-year follow-up. Shortened CBT treatment protocols tend to prove their efficiency for symptom reduction in BPD. Further research is needed to replicate these results.

Estudio de calidad de la pasteurización Holder de leche materna donada en una unidad de nutrición personalizada neonatal / Quality study of Holder pasteurization of donor human milk in a neonatal personalized nutrition unit

Objetivo: La pasteurización Holder es la técnica utilizada más comúnmente en bancos de leche materna para minimizar el riesgo de transmisión de agentes infecciosos. Se han descrito distintos sistemas de pasteurización, que generalmente emplean agua o aire caliente como fuentes de calor. En el presente estudio, se analizó la calidad de la pasteurización realizada con una nueva pasteurizadora automatizada en seco, en una unidad de nutrición personalizada neonatal que procesa leche materna donada de madres de lactantes nacidos a distintas edades gestacionales y de diferentes edades postnatales.Material y método: Se analizó la temperatura durante las distintas fases de la pasteurización con ocho sondas externas distribuidas uniformemente por toda la pasteurizadora. Se aplicaron los criterios óptimos recomendados por la Asociación Europea de Bancos de Leche (EMBA) para monitorizar la calidad de la pasteurización. También se realizó un análisis de macronutrientes en ocho frascos con distintos volúmenes de leche materna donada antes y después de una pasteurización programada.Resultados: No se objetivaron diferencias significativas en los siguientes parámetros analizados: tiempo de calentamiento de 58°C a 62,5°C, duración de la meseta, temperatura máxima durante la meseta y tiempo de exposición a temperaturas superiores a 58°C. El análisis de macronutrientes reveló diferencias significativas en el contenido graso, pero no en el proteico o el de lactosa.Conclusiones: La pasteurización de leche materna mediante un pasteurizador sin agua cumplió los estándares de calidad recomendados por la EMBA, independientemente de la cantidad de leche procesada en cada frasco y con cambios significativos en el contenido graso, pero no en contenido proteico o de lactosa. (AU)

Objective: Holder pasteurization is the technique used most frequently in milk banks to minimize the risk of transmission of infectious agents. Different pasteurization devices have been described that generally use hot water or air as heat sources. In our study, we analysed the quality of pasteurization achieved with a new automated water-free pasteurizer in a neonatal personalized nutrition unit in which donated milk from mothers of infants delivered at different gestational ages and of different postnatal ages is pasteurized.Material and methods: We analysed the temperatures of different phases of pasteurization with 8 external probes distributed evenly throughout the pasteurizer. We applied the optimal range criteria established by the European Milk Bank Association (EMBA) to assess the quality of pasteurization. We also analysed the macronutrient composition of 8 samples of donor human milk of different volumes before and after automated pasteurization.Results: We did not find no significant differences in the following parameters under study: time from 58°C to 62.5°C, duration of plateau, highest temperature during plateau and length of exposure to temperatures over 58°C. The macronutrient analysis showed significant changes in fat content but not in protein or lactose content.Conclusions: Holder pasteurization of human milk with a water-free pasteurizer met the quality standards recommended by the European Milk Bank Association independently of the quantity of milk pasteurized in each bottle and with significant changes in the fat content but not in the protein or lactose content. (AU)

Quality study of Holder pasteurization of donor human milk in a neonatal personalized nutrition unit.

OBJECTIVE: Holder pasteurization is the technique used most frequently in milk banks to minimize the risk of transmission of infectious agents. Different pasteurization devices have been described that generally use hot water or air as heat sources. In our study, we analysed the quality of pasteurization achieved with a new automated water-free pasteurizer in a neonatal personalized nutrition unit in which donated milk from mothers of infants delivered at different gestational ages and of different postnatal ages is pasteurized. MATERIAL AND METHODS: We analysed the temperatures of different phases of pasteurization with 8 external probes distributed evenly throughout the pasteurizer. We applied the optimal range criteria established by the European Milk Bank Association (EMBA) to assess the quality of pasteurization. We also analysed the macronutrient composition of 8 samples of donor human milk of different volumes before and after automated pasteurization. RESULTS: We did not find significant differences in the following parameters under study: time from 58 °C to 62.5 °C, duration of plateau, highest temperature during plateau and length of exposure to temperatures over 58 °C. The macronutrient analysis showed significant changes in fat content but not in protein or lactose content. CONCLUSIONS: Holder pasteurization of human milk with a water-free pasteurizer met the quality standards recommended by the European Milk Bank Association independently of the quantity of milk pasteurized in each bottle and with significant changes in the fat content but not in the protein or lactose content.

[Quality study of Holder pasteurization of donor human milk in a neonatal personalized nutrition unit]. / Estudio de calidad de la pasteurización Holder de leche materna donada en una unidad de nutrición personalizada neonatal.

OBJECTIVE: Holder pasteurization is the technique used most frequently in milk banks to minimize the risk of transmission of infectious agents. Different pasteurization devices have been described that generally use hot water or air as heat sources. In our study, we analysed the quality of pasteurization achieved with a new automated water-free pasteurizer in a neonatal personalized nutrition unit in which donated milk from mothers of infants delivered at different gestational ages and of different postnatal ages is pasteurized. MATERIAL AND METHODS: We analysed the temperatures of different phases of pasteurization with 8 external probes distributed evenly throughout the pasteurizer. We applied the optimal range criteria established by the European Milk Bank Association (EMBA) to assess the quality of pasteurization. We also analysed the macronutrient composition of 8 samples of donor human milk of different volumes before and after automated pasteurization. RESULTS: We did not find no significant differences in the following parameters under study: time from 58°C to 62.5°C, duration of plateau, highest temperature during plateau and length of exposure to temperatures over 58°C. The macronutrient analysis showed significant changes in fat content but not in protein or lactose content. CONCLUSIONS: Holder pasteurization of human milk with a water-free pasteurizer met the quality standards recommended by the European Milk Bank Association independently of the quantity of milk pasteurized in each bottle and with significant changes in the fat content but not in the protein or lactose content.

Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer.

Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of-but not all-spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.

Comparing impulsivity in borderline personality, schizophrenia and obsessional-compulsive disorders: Who is ahead?

OBJECTIVE: Impulsivity impacts life domains and in a psychiatric context is often associated with disorders severity and stigmatization. Borderline personality disorder's (BPD), Schizophrenic disorder's (SZD), and obsessional compulsive disorder's (OCD) impulsivity issues relate to worse prognosis. This study aims to compare these disorders assessing their proneness to impulsivity and urgency. METHODS: We recruited 90 patients among them OCD (n = 25), SZD (n = 23), and BPD (n = 50), and 24 healthy control participants (HC). We assessed the diagnosis according and measured the impulsivity level. RESULTS: Our results showed that BPD was significantly more impulsive than HC, SZD, and OCD. HC, SZD, and OCD being equivalent on their global Urgency-Premeditation-Perseverance-Sensation seeking scores. For urgency, BPD was also superior to others, OCD was superior to HC, but SZD and HC were equivalent. The urgency was correlated to SZD's scale for SZD, no link appeared between borderline personality questionnaire and Yale-Brown Obsessive-Compulsive Scale's score. CONCLUSION: These results question the existent literature relating impulsivity and SZD.

Human milk bank and personalized nutrition in the NICU: a narrative review.

The number of infants born preterm including extremely premature babies is rising worldwide, particularly in low- and middle-income countries, which challenge neonatologists and milk banks for the provision of the most adequate nutrition for successful infant's growth and development. The benefits of mother's own milk (MOM) have been extensively recognized, but the use of donor milk (DM) is a commonly routine practice in preterm neonates admitted to the NICU. Pasteurized mature milk from milk banks is not the same composition than the mother's colostrum and premature milk, the characteristics of which protect the infant from the risk for necrotizing enterocolitis, late-onset sepsis, and other comorbidities associated with prematurity. The development of a personalized nutrition unit (PNU) allows to obtain DM from mothers who have their infants admitted to the NICU and produce an excess of milk, a practice that matches MOM by gestational age and the stage of lactation, ensuring an adequate composition of DM to target the nutritional requirements of premature infants.Conclusion: This narrative review presents salient data of our current knowledge and concerns regarding milk feeding of preterm infants in the NICU, with special emphasis on personalized DM as a result of establishing a PNU. What is Known: • Donor milk bank is mature or pooled milk from lactating mothers at different stages of lactation. • Milk composition varies by gestational age and stage of lactation. What is New: • Donor milk from mothers delivered prematurely have the most adequate composition for preterm infant feeding. • Personalized nutrition for premature infants with preterm donor milk is feasible.

Leche materna descremada en recién nacidos con quilotórax: opciones con una unidad de nutrición personalizada / Skimmed breast milk in newborns with chylothorax: Options with a personalised nutrition unit

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Development of a standardized method to evaluate the protective efficiency of cosmetic packaging against microbial contamination.

Doubts surrounding the potential adverse effects of antimicrobial preservatives have modified the demand of consumers, who increasingly insist on the production of low-level and even preservative-free cosmetics. Protection of the product against microbial contamination is therefore focused on the packaging. This has prompted the emergence of a highly diverse array of so-called "protective", "overprotective", and "barrier" packaging. However, these designations are not normalized and the choice of the right packaging adapted to each cosmetic product is still essentially empirical, hazardous, and time consuming. The Cosmetic Valleys cluster has launched a commission to define a complete and experimentally-validated method to classify the level of protection of cosmetic packaging against microbial contamination. As reported herein, this required the development a specific bacteriostatic medium that can be used for 7 days and an in vitro procedure that reproduces in-use contamination and consumer practices. Based on tests performed on over 800 packages of different origin and performance characteristics, we propose a classification, divided into six grades, to differentiate the protective efficiency of cosmetic packaging. This work can be considered as a first step towards a regulatory text.

Corrigendum to "Impulsivity issues in borderline personality disorder and it's links with insight: the role of urgency"[Heliyon Volume 5, Issue 10, October 2019, e02564].

[This corrects the article DOI: 10.1016/j.heliyon.2019.e02564.].

Impulsivity issues in borderline personality disorder and it's links with insight: the role of urgency.

OBJECTIVE: Impulsivity plays a major role in a wide range of disorders including Borderline Personality Disorder. Another crucial clinical dimension is insight. This clinical dimension is linked with symptomatology and treatment issue. The present study aims to investigate the impact of positive and negative urgency on insight in Borderline Personality Disorder. METHODS: We recruited eighty-one women with Borderline Personality Disorder and assessed insight level and impulsivity scores using the Beck Cognitive insight scale and the UPPS-short form scale. RESULTS: Our results showed interesting links between positive urgency and insight quality. CONCLUSION: Negative emotions play a fundamental role for the insight quality, but positive emotions are surprisingly related to clinical insight. We discuss the possible therapeutical impact of this results on treatment adaptation.

Impact of Cardiac Resynchronization Therapy on Daily Physical Activity in Heart Failure Patients.

PURPOSE: Cardiac resynchronization therapy (CRT) has emerged as a beneficial therapy for heart failure (HF) patients. It has been shown to enhance cardiac pump function and increase exercise capacity in patients with HF who display wide QRS complex on their electrocardiogram. To date, few studies have assessed daily physical activity (PA) in CRT patients. The objective of this pilot study was to assess the impact of CRT on the physical function and daily PA of HF patients who met the standard indications for CRT implantation. METHODS: The daily PA of 18 CRT patients was measured using a SenseWear Armband for ∼3 d. Daily PA measurements included steps/d and time spent sedentary (≤1.5 metabolic equivalent tasks), in light PA (1.6-2.9 metabolic equivalent tasks), and in moderate-vigorous PA (≥3 metabolic equivalent tasks). To assess exercise capacity, a 6-min walk test was performed pre- and post-CRT. RESULTS: There was no significant change in the 6-min walk test distance from pre- to post-CRT (383 ± 99 m at baseline vs 402 ± 104 m post-CRT). There was a decrease in total steps/d from 3405 ± 2334 pre-CRT to 2553 ± 1692 post-CRT (P = .017). Furthermore, no significant changes were observed pre- to post-CRT with regard to the additional PA assessments. CONCLUSIONS: Our patients exhibited a sedentary lifestyle pre- and post-CRT. These findings underscore the need for a cardiac rehabilitation program that encourages post-CRT patients to decrease sedentary time.