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Findings from a community study of parentally bereaved children demonstrate that forewarning of death is not associated with more favorable mental health outcomes than is sudden death of a parent. The applicability of the of the general anticipatory grief literature to the circumstances of children facing the loss of a parent is called into question, and the need to assess more carefully the effect on children of a parent's protracted terminal illness is emphasized. [ABSTRACT FROM AUTHOR]

Off-target effects present a significant impediment to the safe and efficient use of CRISPR-Cas genome editing. Since off-target activity is influenced by the genomic sequence, the presence of sequence variants leads to varying on- and off-target profiles among different alleles or individuals. However, a reliable tool that quantifies genome editing activity in an allelic context is not available. Here, we introduce CRISPECTOR2.0, an extended version of our previously published software tool CRISPECTOR, with an allele-specific editing activity quantification option. CRISPECTOR2.0 enables reference-free, allele-aware, precise quantification of on- and off-target activity, by using de novo sample-specific single nucleotide variant (SNV) detection and statistical-based allele-calling algorithms. We demonstrate CRISPECTOR2.0 efficacy in analyzing samples containing multiple alleles and quantifying allele-specific editing activity, using data from diverse cell types, including primary human cells, plants, and an original extensive human cell line database. We identified instances where an SNV induced changes in the protospacer adjacent motif sequence, resulting in allele-specific editing. Intriguingly, differential allelic editing was also observed in regions carrying distal SNVs, hinting at the involvement of additional epigenetic factors. Our findings highlight the importance of allele-specific editing measurement as a milestone in the adaptation of efficient, accurate, and safe personalized genome editing., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The European Cooperation in Science and Technology (COST) is an intergovernmental organization dedicated to funding and coordinating scientific and technological research in Europe, fostering collaboration among researchers and institutions across countries. Recently, COST Action funded the "Genome Editing to treat Human Diseases" (GenE-HumDi) network, uniting various stakeholders such as pharmaceutical companies, academic institutions, regulatory agencies, biotech firms, and patient advocacy groups. GenE-HumDi's primary objective is to expedite the application of genome editing for therapeutic purposes in treating human diseases. To achieve this goal, GenE-HumDi is organized in several working groups, each focusing on specific aspects. These groups aim to enhance genome editing technologies, assess delivery systems, address safety concerns, promote clinical translation, and develop regulatory guidelines. The network seeks to establish standard procedures and guidelines for these areas to standardize scientific practices and facilitate knowledge sharing. Furthermore, GenE-HumDi aims to communicate its findings to the public in accessible yet rigorous language, emphasizing genome editing's potential to revolutionize the treatment of many human diseases. The inaugural GenE-HumDi meeting, held in Granada, Spain, in March 2023, featured presentations from experts in the field, discussing recent breakthroughs in delivery methods, safety measures, clinical translation, and regulatory aspects related to gene editing., Competing Interests: P.R. has licensed the PGK:FANCAWpre∗ LV medicinal product and receives funding and equity from Rocket Pharmaceuticals, Inc., patents and royalties, research & consulting funding. D.L. is an inventor on a patent National Institute of Chemistry filed (WO/2021/032759 patent application, European patent application EP 3783104, China patent application CN 114269930 with National Phase entry EP2020756868). R.O.B. holds patents related to CRISPR-Cas genome editing and has equity in Graphite Bio and is consultant for UNIKUM Tx. G.G. holds patents related to CRISPR-Cas genome editing, is an employee of CasZyme, and has equity in CasZyme. S.Q.T. is a co-inventor on patents for GUIDE-seq, CHANGE-seq, and other genome editing technologies and a member of the scientific advisory boards of Prime Medicine and Ensoma. T.C. is a co-inventor on patents for CAST-seq, Abnoba-Seq, and other genome editing technologies, and a member of the scientific advisory boards of Cimeo Therapeutics, Excision BioTherapeutics, and GenCC. A.C. and G.T. are inventors on a patent for MEGA (WO/2023/079285), G.T. is also co-inventor on a patent for CAST-seq., (© 2023 The Author(s).)

RAG2-SCID is a primary immunodeficiency caused by mutations in Recombination-activating gene 2 (RAG2), a gene intimately involved in the process of lymphocyte maturation and function. ex-vivo manipulation of a patient's own hematopoietic stem and progenitor cells (HSPCs) using CRISPR-Cas9/rAAV6 gene editing could provide a therapeutic alternative to the only current treatment, allogeneic hematopoietic stem cell transplantation (HSCT). Here we show an innovative RAG2 correction strategy that replaces the entire endogenous coding sequence (CDS) for the purpose of preserving the critical endogenous spatiotemporal gene regulation and locus architecture. Expression of the corrective transgene leads to successful development into CD3 + TCRαβ + and CD3 + TCRγδ + T cells and promotes the establishment of highly diverse TRB and TRG repertoires in an in-vitro T-cell differentiation platform. Thus, our proof-of-concept study holds promise for safer gene therapy techniques of tightly regulated genes., (© 2023. Springer Nature Limited.)

Genome engineering via targeted nucleases, specifically CRISPR-Cas9, has revolutionized the field of gene therapy research, providing a potential treatment for diseases of the blood and immune system. While numerous genome editing techniques have been used, CRISPR-Cas9 homology-directed repair (HDR)-mediated editing represents a promising method for the site-specific insertion of large transgenes for gene knock-in or gene correction. Alternative methods, such as lentiviral/gammaretroviral gene addition, gene knock-out via non-homologous end joining (NHEJ)-mediated editing, and base or prime editing, have shown great promise for clinical applications, yet all possess significant drawbacks when applied in the treatment of patients suffering from inborn errors of immunity or blood system disorders. This review aims to highlight the transformational benefits of HDR-mediated gene therapy and possible solutions for the existing problems holding the methodology back. Together, we aim to help bring HDR-based gene therapy in CD34 + hematopoietic stem progenitor cells (HSPCs) from the lab bench to the bedside.

A model of time-limited intervention groups for parentally bereaved children is described, and common emergent themes are discussed. These suggest that youngsters continue to struggle with death-related stress well beyond the time of the loss. The need to maintain an emotional attachment to internal representations of the deceased parent appears to be an important component of the bereavement process.

Objective: Mental health specialists (N = 48) were surveyed as to (1) their estimates of the likelihood that a 3-year-old child had been sexually molested (as alleged by her mother in the context of a child custody dispute) by her father, and (2) their recommendations, given their estimates, as to child visitation/custody., Method: Specialists heard a detailed presentation of the court-appointed clinician's findings in this case, which included parent interviews and videotaped child-parent interaction sequences., Results: The array of estimated likelihoods was extreme despite that all the clinicians heard the same case. Recommendations to the court strongly tended toward restriction of child-father contact, even when estimates of the likelihood of abuse were low., Conclusions: Courts should be highly cautious in relying on clinical experts in child custody cases entailing allegations of child sexual abuse. Practitioners should be candid with courts concerning the absence of diagnostic precision in such cases.

Individual differences in exposure and response to stress in a sample of 56 divorced mothers were examined. Compared with normative data, the sample reported significantly more negative life events, more psychiatric symptoms, and poorer social adjustment. Social support and income emerged as the mediating factors most strongly associated with adjustment outcome.

Experts in clinical evaluations of child sexual abuse were studied using a paradigm that requested them to estimate the likelihood of a 3-year-old child having been sexually molested by her father, as alleged by her mother, when she was two years old. All of the experts claimed special qualifications and experience in the field of diagnosing and treating child sexual abuse victims. Expert-respondents provided two estimates of the likelihood that the child had been molested, the first following a detailed presentation of the clinical case by the actual evaluator of the child (the presentation included opportunities to ask questions ad libitum beyond the presentation material), the second following an extensive discussion of the clinical material with other child experts present. The range of estimated likelihoods that the child had been molested was extreme among the expert respondents. The clinical conference format that was used seemed to provide the experts with no apparent means for eliminating or reducing differences in their clinical opinions. Recommendations concerning how the supervising court should regulate further child-father contacts were similarly varied. The implications of these findings for judicial acceptance of expert testimony in cases of alleged child sexual abuse are discussed.

Fifty-three fourth- and fifth grade children were tested on postdivorce adjustment immediately before and six months after participation in an eight-week preventive intervention program. At follow-up, most showed positive change, with those at special risk for adjustment problems showing substantial gains. Results did not vary with sociodemographic or divorce circumstances.

The general quality of latency-aged children's prognostic thinking and the way in which they view the long-range impact of divorce upon peer adaptation are explored. When interviewed about responses to two fictional peers with marked behavior problems, 80 children in the third and fifth grades displayed an optimism in their prognostic thinking about the future of these peers. In general, peers from divorced homes were perceived as having a more positive future adjustment than peers from intact homes. However, male subjects from disrupted homes revealed a significantly pessimistic orientation regarding the impact of divorce upon the future; females from disrupted homes had a strikingly optimistic view. Implications for school-based interventions are discussed.

This study focuses on children from multiproblem families when they appear at an outpatient psychiatric clinic for children. The sample consisted of the first 50 children and their families referred to a large children's outpatient psychiatric facility early in 1974. A multiproblem family was defined in terms of the number of helping agencies and/or professionals contacted by family members within the 3-year period prior to the current psychiatric evaluation and by the number of households in which the designated child patient had lived. Eighteen percent of the 50 cases met the criteria established for a multiproblem family. These indicators successfully differentiated multiproblem from nonmultiproblem families along a number of socioeconomic, demographic, family health, and family stability dimensions. Special difficulties encountered in psychiatrically evaluating children of such multiproblem families are presented, and ways of dealing with them are discussed.

Laboratory test results for the diagnosis of psychiatric illness usually are reported descriptively despite the ready availability of appropriate inferential statistics. A test's sensitivity, specificity, and diagnostic confidence are conditional probabilities. Confidence intervals may be calculated for these probabilities in any given study. Statistical tests for comparing the results of several studies use techniques for planned and posterior comparisons applied to contingency tables. These established statistical methods aid in the interpretation of laboratory test findings.

A model of time-limited, school-based groups for children of divorce is presented. Common themes that emerged in groups conducted in three schools suggest that youngsters continue to wrestle with divorce-related conflicts years after the marital disruption. Developmental tasks created by specific post-divorce stresses are described, and multiple brief interventions tied to nodal points in child development are proposed.

Recent reports suggest that divorce is a significant developmental stress for most children. Preventive intervention programs aimed at mitigating both short- and long-term divorce sequelae for children are now widespread. Considerably less attention has been paid to youngsters in need of clinical services years after parental separation. In this paper, adolescent daughters of divorced parents are described in the context of a proposed conjoint mother-daughter intervention.

Despite increasing recognition of the early importance of peer relations, virtually no systematic information exists on the way in which normal children view their emotionally disturbed peers. This paper reports a replication of recent findings on children's use of the concept of emotional disturbance. Ss were 40 fourth and sixth graders. Five vignettes that described one normal and four emotionally disturbed boys were read to individual Ss; who were interviewed about their understanding of the central figures (CFs). Interviews were coded to a 5-point scale of degree of perceived emotional disturbance. Earlier findings were replicated to a remarkable degree. Ss differentiated among the CFs in a manner congruent with clinician judges' ratings. Grade differences indicate the differential attention to and valuing of specific behaviors, rather than global differences in perception of emotional disturbance.

The literature on children of divorce presents three theories on the relationship between a child's age at divorce and subsequent adaptation. Outpatient evaluations of 144 children of divorce, ranging in age from seven to 17 years, were coded for nature of emotional-behavioral problems and overall degree of psychological adjustment. Divorce timing was unrelated to overall level of adjustment, but was associated significantly with different constellations of emotional-behavioral difficulties.

Six hypotheses to explain how divorce may affect the trajectory of child development were tested using standardized measures and sociodemographic data. Correlational and multiple regression analyses revealed that the parent adjustment hypothesis received the strongest support. Boys appeared sensitive to events and behavior in their mothers' lives, while girls seemed attuned to mothers' internal states.

In a review of the records of some 400 children referred for outpatient psychiatric evaluation, children of divorce appeared at nearly twice the rate of their occurrence in the general population. Age and sex of the child patient were found to relate substantially to parental status, and to be significantly associated with type of presenting symptom. It is suggested that earlier research into the relationship between symptomology and history of divorce may have been marred by failure to take into account age and sex factors.

Scores on the Nowicki-Strickland Locus of Control Scale for Children (N-SLOCSC) were compared for third and fifth grade boys and girls from intact versus maritally disrupted family backgrounds. Significant main effects for each independent variable revealed that fifth graders more than third, boys more than girls, and the marital disruption more than the intact group, exhibited higher internality in their locus of control scores. These findings strongly suggest that experiencing a parental divorce in childhood has a significant influence on generalized perceptions of personal control and effectance, perceptions which may ultimately mediate both short- and long-term outcomes in children's post-divorce adjustment.

Research and clinical work with children of divorce have focused primarily on parental separation as a traumatic event and its effects on children as a crisis situation. The present paper, based on clinical experience, considers potential long-term problems of these children in key developmental areas: handling anger and aggression, separation-individuation, and gender identity. Implications for prevention and service delivery are presented.

In a previous study, we (Marsden and Kalter, 1976) found that fourth- and sixth-grade children not only made distinctions between normal and emotionally disturbed behavior, but also were able to discriminate degrees of childhood psychopathology in a manner strikingly congruent with clinician-judges. Having assessed children's perceptions of emotional disturbance, we turned our attention to how the children might account for the development of such childhood disorders. We are aware of no previous study which has examined children's views of the etiology of emotionally disturbed behavior of their peers. Such information could shed further light on children's understanding of childhood psychopathology and might implicitly indicate what children believe are the necessary ingredients for healthy emotional development. This knowledge would be useful to mental health professionals, teachers, and parents seeking both to understand the emotionally disturbed child's place in his peer group and to convey an understanding of emotional illness to normal children.