Detecting measurable residual disease beyond 10-4 by an IGHV leader-based NGS approach improves prognostic stratification in CLL.

The sensitivity of conventional techniques for reliable quantification of minimal/measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is limited to MRD 10-4. Measuring MRD <10-4 could help to further distinguish between patients with CLL with durable remission and those at risk of early relapse. We herein present an academically developed immunoglobulin heavy-chain variable (IGHV) leader-based next-generation sequencing (NGS) assay for the quantification of MRD in CLL. We demonstrate, based on measurements in contrived MRD samples, that the linear range of detection and quantification of our assay reaches beyond MRD 10-5. If provided with sufficient DNA input, MRD can be detected down to MRD 10-6. There was high interassay concordance between measurements of the IGHV leader-based NGS assay and allele-specific oligonucleotide quantitative polymerase chain reaction (PCR) (r = 0.92 [95% confidence interval {CI}, 0.86-0.96]) and droplet digital PCR (r = 0.93 [95% CI, 0.88-0.96]) on contrived MRD samples. In a cohort of 67 patients from the CLL11 trial, using MRD 10-5 as a cutoff, undetectable MRD was associated with superior progression-free survival (PFS) and time to next treatment. More important, deeper MRD measurement allowed for additional stratification of patients with MRD <10-4 but ≥10-5. PFS of patients in this MRD range was significantly shorter, compared with patients with MRD <10-5 (hazard ratio [HR], 4.0 [95% CI, 1.6-10.3]; P = .004), but significantly longer, compared with patients with MRD ≥10-4 (HR, 0.44 [95% CI, 0.23-0.87]; P = .018). These results support the clinical utility of the IGHV leader-based NGS assay.

Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome.

Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.

Incorporating Anti-racist Principles Throughout the Research Lifecycle: A Position Statement from the Society of General Internal Medicine (SGIM).

Biomedical research has advanced medicine but also contributed to widening racial and ethnic health inequities. Despite a growing acknowledgment of the need to incorporate anti-racist objectives into research, there remains a need for practical guidance for recognizing and addressing the influence of ingrained practices perpetuating racial harms, particularly for general internists. Through a review of the literature, and informed by the Research Lifecycle Framework, this position statement from the Society of General Internal Medicine presents a conceptual framework suggesting multi-level systemic changes and strategies for researchers to incorporate an anti-racist perspective throughout the research lifecycle. It begins with a clear assertion that race and ethnicity are socio-political constructs that have important consequences on health and health disparities through various forms of racism. Recommendations include leveraging a comprehensive approach to integrate anti-racist principles and acknowledging that racism, not race, drives health inequities. Individual researchers must acknowledge systemic racism's impact on health, engage in self-education to mitigate biases, hire diverse teams, and include historically excluded communities in research. Institutions must provide clear guidelines on the use of race and ethnicity in research, reject stigmatizing language, and invest in systemic commitments to diversity, equity, and anti-racism. National organizations must call for race-conscious research standards and training, and create measures to ensure accountability, establishing standards for race-conscious research for research funding. This position statement emphasizes our collective responsibility to combat systemic racism in research, and urges a transformative shift toward anti-racist practices throughout the research cycle.

How to Create a Diversity, Equity, and Inclusion Curriculum: More Than Checking a Box.

We are beginning to accept and address the role that medicine as an institution played in legitimizing scientific racism and creating structural barriers to health equity. There is a call for greater emphasis in medical education on explaining our role in perpetuating health inequities and educating learners on how bias and racism lead to poor health outcomes for historically marginalized communities. Diversity, equity, and inclusion (DEI; also referred to as EDI) and antiracism are key parts of patient care and medical education as they empower health professionals to be advocates for their patients, leading to better health care outcomes and more culturally and socially humble health care professionals. The Liaison Committee on Medical Education has set forth standards to include structural competency and other equity principles in the medical curriculum, but medical schools are still struggling with how to specifically do so. Here, we highlight a stepwise approach to systematically developing and implementing medical educational curriculum content with a DEI and antiracism lens. This article serves as a blueprint to prepare institution leadership, medical faculty, staff, and learners in how to effectively begin or scale up their current DEI and antiracism curricular efforts.

BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening.

There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice.

Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingolipid balance underlies regional sensitivity to pathological insults. Here, we investigated the regional compartmentalization of sphingolipids and their related enzymes in the cerebellar cortex in healthy and pathological conditions. Analysis in wild-type animals revealed higher sphingosine kinase 1 (Sphk1) levels in the flocculonodular cerebellum, while sphingosine-1-phosphate (S1P) levels were higher in the anterior cerebellum. Next, we investigated a model for spinocerebellar ataxia type 1 (SCA1) driven by the transgenic expression of the expanded Ataxin 1 protein with 82 glutamine (82Q), exhibiting severe PC degeneration in the anterior cerebellum while the flocculonodular region is preserved. In Atxn1[82Q]/+ mice, we found that levels of Sphk1 and Sphk2 were region-specific decreased and S1P levels increased, particularly in the anterior cerebellum. To determine if there is a causal link between sphingolipid levels and neurodegeneration, we deleted the Sphk1 gene in Atxn1[82Q]/+ mice. Analysis of Atxn1[82Q]/+; Sphk1-/- mice confirmed a neuroprotective effect, rescuing a subset of PCs in the anterior cerebellum, in domains reminiscent of the modules defined by AldolaseC expression. Finally, we showed that Sphk1 deletion acts on the ATXN1[82Q] protein expression and prevents PC degeneration. Taken together, our results demonstrate that there are regional differences in sphingolipid metabolism and that this metabolism is directly involved in PC degeneration in Atxn1[82Q]/+ mice.

Health Justice Standards in Graduate Medical Education: Moving from Performative to Concrete Change.

BACKGROUND: Inadequate support for underrepresented-in-medicine physicians, lack of physician knowledge about structural drivers of health, and biased patient care and research widen US health disparities. Despite stating the importance of health equity and diversity, national physician education organizations have not yet prioritized these goals. AIM: To develop a comprehensive set of Health Justice Standards within our residency program to address structural drivers of inequity. SETTING: The J. Willis Hurst Internal Medicine Residency Program of Emory University is an academic internal medicine residency program located in Atlanta, Georgia. PARTICIPANTS: This initiative was led by the resident-founded Churchwell Diversity and Inclusion Collective, modified by Emory IM leadership, and presented to Emory IM residents. PROGRAM DESCRIPTION: We used an iterative process to develop and implement these Standards and shared our progress with our coresidents to evaluate impact. PROGRAM EVALUATION: In the year since their development, we have made demonstrable progress in each domain. Presentation of our work significantly correlated with increased resident interest in advocacy (p<0.001). DISCUSSION: A visionary, actionable health justice framework can be used to generate changes in residency programs' policies and should be developed on a national level.

Management of diabetes patients with comorbidity in primary care: a mixed-method study in Odisha, India.

BACKGROUND: Diabetes patients with comorbidities need regular and comprehensive care for their disease management. Hence, it is essential to assess the primary care preparedness for managing diabetes patients and the perspectives of the diabetes patients on the care received at the primary care facilities. METHODS: All 21 Urban Primary Health Centres (UPHCs) in Bhubaneswar city of Odisha, India, were assessed using the modified Primary Care Evaluation Tool and WHO Package of Essential Non-communicable disease interventions questionnaire. Additionally, 21 diabetes patients with comorbidities were interviewed in-depth to explore their perception of the care received at the primary care facilities. RESULTS: All the UPHCs had provisions to meet the basic requirements for the management of diabetes and common comorbidities like hypertension. There were few provisions for chronic kidney illness, cardiovascular disease, mental health, and cancer. Diabetes patients felt that frequent change in primary care physicians at the primary care facilities affected their continuity of care. Easy accessibility, availability of free medicines, and provisions of basic laboratory tests at the facilities were felt to be necessary by the diabetes patients. CONCLUSION: Our study highlights the existing gaps in India's healthcare system preparedness and the needs of diabetes patients with comorbidity. The government of India's Health and Wellness (HWC) scheme aims to deliver comprehensive healthcare to the population and provide holistic care at the primary care level for NCD patients. It is imperative that there is an early implementation of the various components of the HWC scheme to provide optimal care to diabetes patients.

Molecular Minimal Residual Disease in Acute Myeloid Leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in virtually every patient, but its clinical value for the prediction of relapse has yet to be established. METHODS: We conducted a study involving patients 18 to 65 years of age who had newly diagnosed AML. Targeted next-generation sequencing was carried out at diagnosis and after induction therapy (during complete remission). End points were 4-year rates of relapse, relapse-free survival, and overall survival. RESULTS: At least one mutation was detected in 430 out of 482 patients (89.2%). Mutations persisted in 51.4% of those patients during complete remission and were present at various allele frequencies (range, 0.02 to 47%). The detection of persistent DTA mutations (i.e., mutations in DNMT3A, TET2, and ASXL1), which are often present in persons with age-related clonal hematopoiesis, was not correlated with an increased relapse rate. After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate than no detection (55.4% vs. 31.9%; hazard ratio, 2.14; P<0.001), as well as with lower rates of relapse-free survival (36.6% vs. 58.1%; hazard ratio for relapse or death, 1.92; P<0.001) and overall survival (41.9% vs. 66.1%; hazard ratio for death, 2.06; P<0.001). Multivariate analysis confirmed that the persistence of non-DTA mutations during complete remission conferred significant independent prognostic value with respect to the rates of relapse (hazard ratio, 1.89; P<0.001), relapse-free survival (hazard ratio for relapse or death, 1.64; P=0.001), and overall survival (hazard ratio for death, 1.64; P=0.003). A comparison of sequencing with flow cytometry for the detection of residual disease showed that sequencing had significant additive prognostic value. CONCLUSIONS: Among patients with AML, the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame. (Funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and others.).

Cost-effectiveness of a stepwise cardiometabolic disease prevention program: results of a randomized controlled trial in primary care.

BACKGROUND: Cardiometabolic diseases (CMD) are the major cause of death worldwide and are associated with a lower quality of life and high healthcare costs. To prevent a further rise in CMD and related healthcare costs, early detection and adequate management of individuals at risk could be an effective preventive strategy. The objective of this study was to determine long-term cost-effectiveness of stepwise CMD risk assessment followed by individualized treatment if indicated compared to care as usual. A computer-based simulation model was used to project long-term health benefits and cost-effectiveness, assuming the prevention program was implemented in Dutch primary care. METHODS: A randomized controlled trial in a primary care setting in which 1934 participants aged 45-70 years without recorded CMD or CMD risk factors participated. The intervention group was invited for stepwise CMD risk assessment through a risk score (step 1), additional risk assessment at the practice in case of increased risk (step 2) and individualized follow-up treatment if indicated (step 3). The control group was not invited for risk assessment, but completed a health questionnaire. Results of the effectiveness analysis on systolic blood pressure (- 2.26 mmHg; 95% CI - 4.01: - 0.51) and total cholesterol (- 0.15 mmol/l; 95% CI - 0.23: - 0.07) were used in this analysis. Outcome measures were the costs and benefits after 1-year follow-up and long-term (60 years) cost-effectiveness of stepwise CMD risk assessment compared to no assessment. A computer-based simulation model was used that included data on disability weights associated with age and disease outcomes related to CMD. Analyses were performed taking a healthcare perspective. RESULTS: After 1 year, the average costs in the intervention group were 260 Euro higher than in the control group and differences were mainly driven by healthcare costs. No meaningful change was found in EQ 5D-based quality of life between the intervention and control groups after 1-year follow-up (- 0.0154; 95% CI - 0.029: 0.004). After 60 years, cumulative costs of the intervention were 41.4 million Euro and 135 quality-adjusted life years (QALY) were gained. Despite improvements in blood pressure and cholesterol, the intervention was not cost-effective (ICER of 306,000 Euro/QALY after 60 years). Scenario analyses did not allow for a change in conclusions with regard to cost-effectiveness of the intervention. CONCLUSIONS: Implementation of this primary care-based CMD prevention program is not cost-effective in the long term. Implementation of this program in primary care cannot be recommended. TRIAL REGISTRATION: Dutch Trial Register NTR4277 , registered on 26 November 2013.

Characteristics and motives of non-responders in a stepwise cardiometabolic disease prevention program in primary care.

BACKGROUND: A high response rate is an important condition for effective prevention programs. We aimed at gaining insight into the characteristics and motives of non-responders in different stages of a stepwise prevention program for cardiometabolic diseases (CMD) in primary care. METHODS: We performed a non-response analysis within a randomized controlled trial assessing the effectiveness of a stepwise CMD prevention program in the Netherlands. Patients between 45 and 70 years without known CMD were invited for stage 1 of the program, completing a CMD risk score. Patients with an increased risk were advised to visit their general practice for additional measurements, stage 2 of the program. We analyzed determinants of non-response using data from the risk score, electronic medical records, questionnaires and Statistics Netherlands. RESULTS: Non-response in stage 1 was associated with a younger age, male sex, a migration background, a low prosperity score, self-employment, being single and having lower consultations rates in general practice. Non-response in stage 2 was associated with a low prosperity score, being employed, having no chronic illness, smoking, a normal waist circumference, a negative family history for cardiovascular disease or diabetes and having a lower consultation rate. More than half of the non-responders in stage 2 reported not visiting the GP because they did not expect to have any CMD, despite their increased risk. CONCLUSIONS: To achieve a larger and more equal uptake of prevention programs for CMD, we should use methods adapted to characteristics of non-responders, such as targeted invitation methods and improved risk communication.

Optimising personal continuity for older patients in general practice: a study protocol for a cluster randomised stepped wedge pragmatic trial.

BACKGROUND: Continuity of care, in particular personal continuity, is a core principle of general practice and is associated with many benefits such as a better patient-provider relationship and lower mortality. However, personal continuity is under pressure due to changes in society and healthcare. This affects older patients more than younger patients. As the number of older patients will double the coming decades, an intervention to optimise personal continuity for this group is highly warranted. METHODS: Following the UK Medical Research Council framework for complex Interventions, we will develop and evaluate an intervention to optimise personal continuity for older patients in general practice. In phase 0, we will perform a literature study to provide the theoretical basis for the intervention. In phase I we will define the components of the intervention by performing surveys and focus groups among patients, general practitioners, practice assistants and practice nurses, concluded by a Delphi study among members of our group. In phase II, we will test and finalise the intervention with input from a pilot study in two general practices. In phase III, we will perform a stepped wedge cluster randomised pragmatic trial. The primary outcome measure is continuity of care from the patients' perspective, measured by the Nijmegen Continuity Questionnaire. Secondary outcome measures are level of implementation, barriers and facilitators for implementation, acceptability and feasibility of the intervention. In phase IV, we will establish the conditions for large-scale implementation. DISCUSSION: This is the first study to investigate an intervention for improving personal continuity for older patients in general practice. If proven effective, our intervention will enable General practitioners to improve the quality of care for their increasing population of older patients. The pragmatic design of the study will enable evaluation in real-life conditions, facilitating future implementation. TRIAL REGISTRATION NUMBER: Netherlands Trial Register, trial NL8132 . Registered 2 November 2019.

Transcending boundaries for collaborative patient care.

Dutch general practitioners (GPs) and medical specialists (MSs) create collaborative patient care agreements (CPCAs) to improve intraprofessional collaboration. We set out to identify contradictions between the activity systems of primary and secondary care that could result in expansive learning and new ways of working collaboratively. We analysed nineteen semi-structured interviews using activity theory (AT) as a theoretical framework and using these two activity systems as the units of analysis. There were contradictions within and between the activity systems related, for example, to different understandings of 'care' in generalist and specialist settings. GPs and MSs were able to identify contradictions and learn expansively when they iteratively co-created CPCAs in groups. They found it much harder to tackle contradictions, however, when they disseminated these tools within their respective professional communities, leaving unresolved contradictions and missed opportunities for collaboration. This research shows the educational benefits of taking collective responsibility for improving collaborative patient care.

Income-related differences in out-of-hours primary care telephone triage using national registration data.

BACKGROUND: Telephone triage is used to facilitate efficient and adequate acute care allocation, for instance in out-of-hours primary care services (OPCSs). Remote assessment of health problems is challenging and could be impeded by a patient's ambiguous formulation of his or her healthcare need. Socioeconomically vulnerable patients may experience more difficulty in expressing their healthcare need. We aimed to assess whether income differences exist in the patient's presented symptoms, assessed urgency and allocation of follow-up care in OPCS. METHOD: Data were derived from Nivel Primary Care Database encompassing electronic health record data of 1.3 million patients from 28 OPCSs in 2017 in the Netherlands. These were linked to sociodemographic population registry data. Multilevel logistic regression analyses (contacts clustered in patients), adjusted for patient characteristics (eg, age, sex), were conducted to study associations of symptoms, urgency assessment and follow-up care with patients' income (standardised for household size as socioeconomic status (SES) indicator). RESULTS: The most frequently presented symptoms deduced during triage slightly differed across SES groups, with a larger relative share of trauma in the high-income groups. No SES differences were observed in urgency assessment. After triage, low income was associated with a higher probability of receiving telephone advice and home visits, and fewer consultations at the OPCS. CONCLUSIONS: SES differences in the patient's presented symptom and in follow-up in OPCS suggest that the underlying health status and the ability to express care needs affect the telephone triage process . Further research should focus on opportunities to better tailor the telephone triage process to socioeconomically vulnerable patients.

Effect of S-Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor.

In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3-8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp2 of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A2A receptor (A2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1-8). However, the N-methylated compounds (2, 6-8) presented a weak partial agonist profile at A2AR, contrary to the non-methylated counterparts (1, 3-5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.

[Did child-psychiatry patients really experience the dreaded clinical degradation during the COVID-19 pandemic lockdown?] / Les enfants suivis en psychiatrie infanto-juvénile ont ils connu la dégradation redoutée pendant la période de confinement liée à la pandémie COVID-19 ?

BACKGROUND: The general lockdown period during the COVID-19 pandemic which covered mid-March to mid-May 2020 in France raised important questions about the direct and indirect psychological effects on children and adolescents. Perceived intuitively as harmful and even traumatic in the media's discourse, we tried to better qualify its effects from two complementary approaches. We carried out a review of the literature on the subject to which we associated a regular assessment of the children's global clinical state in the entire active file of the child-psychiatry department of the Centre Hospitalier Universitaire de Brest throughout the lockdown period.The findings of the literature review on the psychological effects of lockdowns or quarantines during past or current epidemics, in particular in China, report many deleterious and variable effects such as symptoms of anxiety, depression, as well as Post Traumatic Stress Disorder, at a significant rate. However, the definition of the situations experienced and the contexts in which those studies took place appear to be not truly comparable to the French situation. Moreover, the effects of the fear of contamination are not differentiated from those linked to confinement itself. PATIENTS AND METHODS: Among children and adolescents under the care of the above department, 354 underwent an assessment of the impact of lockdown on their global clinical condition using the Clinical Global Impression Improvement (CGI-I) performed by their usual practitioner during the period from March 16 to May 11, 2020. RESULTS: Our results highlight that 50% of children remained in stable condition, 25 to 30% improved and 20 to 25% experienced a slight degradation. The evolution of the clinical status appeared stable over time during the eight weeks. The initial age or severity of mental disorder had no significant influence, although there was a slightly more frequent improvement in adolescents. CONCLUSION: These results are quite inconsistent with general discourse and common expectations. Several psychopathological hypotheses are discussed to support this absence of psychological degradation which might even be extended to children and adolescents in the general population.

MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.

The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic profiling of 3 early-onset acute myeloid leukemias (AMLs) identified germ line loss of MBD4 as an initiator of 5mC-dependent hypermutation. MBD4-deficient AMLs display a 33-fold higher mutation burden than AML generally, with >95% being C>T in the context of a CG dinucleotide. This distinctive signature was also observed in sporadic cancers that acquired biallelic mutations in MBD4 and in Mbd4 knockout mice. Sequential sampling of germ line cases demonstrated repeated expansion of blood cell progenitors with pathogenic mutations in DNMT3A, a key driver gene for both clonal hematopoiesis and AML. Our findings reveal genetic and epigenetic factors that shape the mutagenic influence of 5mC. Within blood cells, this links methylation damage to the driver landscape of clonal hematopoiesis and reveals a conserved path to leukemia. Germ line MBD4 deficiency enhances cancer susceptibility and predisposes to AML.

Effectiveness of a stepwise cardiometabolic disease prevention program: Results of a randomized controlled trial in primary care.

Effective preventive strategies for cardiometabolic disease (CMD) are needed. We aim to establish the effectiveness of a stepwise CMD risk assessment followed by individualized treatment if indicated compared to care as usual. We conducted a RCT between 2014 and 2017. Individuals (45-70 years) without CMD or CMD risk factors were invited for stepwise CMD risk assessment through a risk score (step1), additional risk assessment at the practice in case of high-risk (step2) and individualized follow-up treatment if indicated (step3). We compared newly detected CMD and newly prescribed drugs during one-year follow-up, and change in CMD risk profile between baseline and one-year follow-up among participants who completed step2 to matched controls. A CMD was diagnosed almost three times more often (OR 2.90, 95% CI 2.25: 3.72) in the intervention compared to the control group, in parallel with newly prescribed antihypertensive and lipid lowering drugs (OR 2.85, 95% CI 1.96: 4.15 and 3.23, 95% CI 2.03: 5.14 respectively). Waist circumference significantly decreased between the intervention compared to the control group (mean -3.08 cm, 95% CI -3.73: -2.43). No differences were observed for changes in BMI and smoking. Systolic blood pressure (mean -2.26 mmHg, 95% CI -4.01: -0.51) and cholesterol ratio (mean -0.11, 95% CI -0.19: -0.02) significantly decreased within intervention participants between baseline and one-year follow-up. In conclusion, implementation of the CMD prevention program resulted in the detection of two- to threefold more patients with CMD. A significant drop in systolic blood pressure and cholesterol levels was found after one year of treatment. Modelling of these results should confirm the effect on long term endpoints. Trial registration: Dutch trial Register number NTR4277.