Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations.

Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Toward this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with a homozygous frameshift mutation (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of subretinal deposits near the optic disc, disruption of the outer retina, and neurosensorial detachment, whereas the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP and provide a toolkit and preclinical data for advancing therapeutic approaches.

'Something that helped the whole picture': Experiences of parents offered rapid prenatal exome sequencing in routine clinical care in the English National Health Service.

OBJECTIVES: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent experiences and their information and support needs from the perspective of parents offered pES and of health professionals involved in its delivery. METHODS: In this qualitative study, semi-structured interviews were conducted with 42 women and 6 male partners and 63 fetal medicine and genetic health professionals. Interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: Overall views about pES were positive and parents were grateful to be offered the test. Highlighted benefits of pES included the value of the additional information for pregnancy management and planning for future pregnancies. An anxious wait for results was common, often associated with the need to make decisions near to 24 weeks in pregnancy when there are legal restrictions for late termination. Descriptions of dealing with uncertainty were also common, even when results had been returned. Many parents described pES results as informing decision-making around whether or not to terminate pregnancy. Some professionals were concerned that a non-informative result could be overly reassuring and highlighted that careful counselling was needed to ensure parents have a good understanding of what the result means for their pregnancy. Emotional support from professionals was valued; however, some parents felt that post-test support was lacking. CONCLUSION: Parents and professionals welcomed the introduction of pES. Results inform parents' decision-making around the termination of pregnancy. When there are no diagnostic findings or uncertain findings from pES, personalised counselling that considers scans and other tests are crucial. Directing parents to reliable online sources of information and providing emotional support throughout could improve their experiences of care.

Modeling and design of solar + storage-powered community resilience hubs across California.

Distributed clean, reliable energy resources like solar plus battery storage (solar + storage) can reduce harmful emissions while supporting resilience. Solar + storage-powered resilience hubs provide energy for critical services during disasters while increasing human adaptive capacity year round. We studied where utility rates, local climate, and historical injustice make solar + storage resilience hubs more valuable and more challenging. We modeled the economic and climate impacts of outfitting candidate hub sites across California with solar + storage for everyday operations and identified designs and costs required to withstand a range of outages considering weather impacts on energy needs and availability. We integrated sociodemographic data to prioritize the siting of resilience hubs, to focus potential policy and funding priorities on regions where solar + storage for resilience hubs is hard or expensive, and where populations are most in need. We identified almost 20,000 candidate buildings with more than 8 GW of total rooftop solar potential capable of reducing CO2 emissions by 5 million tons per year while providing energy for community resilience. Hub capacity for one of the most challenging missions-providing emergency shelter during a power outage and smoke event-could have a statewide average lifetime cost of less than $2000 per seat. We identified regional challenges including insufficient rooftop solar capacity in cities, low sunlight in northern coastal California, and high costs driven by utility rate structures in Sacramento and the Imperial Valley. Results show that rates and net metering rules that incentivize solar + storage during everyday operations decrease resilience costs.

The Role of Maternal Anxiety in Treatment Response for Youth with ASD and Co-occurring Anxiety.

Anxiety disorders occur at higher rates in youth with ASD than in neurotypical youth. Although the efficacy of CBT for anxiety in children with ASD is widely supported, factors that influence treatment outcomes are not well understood. This study examined the role of maternal anxiety in treatment outcomes for youth with ASD. Youth with ASD and anxiety (ages 8 to 14), along with their mothers (n = 87), participated in a group CBT intervention. Results indicated that maternal anxiety did not improve over the course of treatment. However, findings suggest that high levels of maternal anxiety at pre-treatment predicted higher levels of youth anxiety post-treatment. Importantly, the relationship between parent anxiety and youth outcomes was moderated by child age. The findings of the present study may provide initial insight into the role that maternal anxiety plays in treatment outcomes for children with ASD and co-occurring anxiety, particularly when considering child age.

A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia.

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.

Group Cognitive Behavioural Treatment for Anxiety in Autistic Adolescents with Intellectual Disability: A Pilot and Feasibility Study.

BACKGROUND: Adolescents with Autism Spectrum Disorder (ASD) and intellectual disability evidence significant anxiety. This study aimed to adapt a group cognitive behaviour therapies (CBT) programme designed for youth with ASD and anxiety to meet the cognitive, communication, and behavioural needs of adolescents with intellectual disability, and assess initial feasibility and efficacy of the intervention. METHODS: Structural, content and procedural adaptations were made to a 14-week family-focused CBT intervention. Twenty-three adolescents with ASD, intellectual disability and anxiety were included. Treatment acceptability along with adolescent anxiety symptoms was assessed via parent report measures. RESULTS: Of the 23 participants, 19 completed treatment and attended 94% of sessions. Parent acceptability was high. Significant reductions were noted on anxiety symptoms post-intervention. CONCLUSIONS: Results indicate that the CBT group was feasible and acceptable. Preliminary outcomes suggest that adolescent anxiety improved, although replication with a larger sample and comparison to a control group is needed.

Peroxy self-reaction leading to the formation of furfural.

Interest in alternative fuels to petroleum and classical fuels has been growing very rapidly in recent years. Furan and its alkyl derivatives, such as methylfuran (2MF), have been identified as valid alternative biofuels. This study focuses on the self-reaction of the peroxy radical generated in the first oxidation step of 2MF, initiated by Cl atoms at 323 K and 4 Torr. The experiments have been carried out by a multiplexed synchrotron photoionization mass spectrometer (mSPIMS) at the Advanced Light Source (ALS) of Lawrence Berkeley National Laboratory (USA). The presence of a peak at m/z = 96 reveals that furfural is the dominant product of 2MF oxidation. Various reaction mechanisms for furfural formation are proposed here. The potential energy surfaces for singlet and triplet spin states have been mapped using quantum mechanical methods, such as CCSD(T), DFT-B3LYP, and composites models (CBS-QB3), to optimize the products, transition states, and intermediates. Experimental and theoretical results provide evidence that furfural does not form by primary reaction chemistry. Self-reaction of the peroxy radical generated in the first oxidation step of 2MF has been proposed as the pathway leading to the formation of furfural. Among various reaction channels, we indentified some entirely exothermic pathways involving oxygen-oxygen coupling and the formation of ROOOOR Russell intermediates.

Deficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesia.

BACKGROUND: Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies. Affected babies die as a result of pulmonary hypoplasia. We aimed to identify the underlying genetic cause of this disorder in a family in which there were three affected individuals from two sibships. METHODS: Autosomal-recessive inheritance was suggested by a family history of consanguinity and by recurrence of the phenotype between the two sibships. We performed exome sequencing of the affected individuals and their unaffected mother, followed by autozygosity mapping and variant filtering to identify the causative gene. RESULTS: Five autozygous regions were identified, spanning 31.7 Mb of genomic sequence and including 211 genes. Using standard variant filtering criteria, we excluded all variants as being the likely pathogenic cause, apart from a single novel nonsense mutation, c.188C>A p.(Ser63*) (NM_002478.4), in MYOD1. This gene encodes an extensively studied transcription factor involved in muscle development, which has nonetheless not hitherto been associated with a hereditary human disease phenotype. CONCLUSIONS: We provide the first description of a human phenotype that appears to result from MYOD1 mutation. The presentation with FADS is consistent with a large body of data demonstrating that in the mouse, MyoD is a major controller of precursor cell commitment to the myogenic differentiation programme.

billingsMentor: Adapting natural family planning to information technology and relieving the user of unnecessary tasks.

BillingsMentor is an automated Web-based service for the Billings Method of natural family planning in which the guidance and interpretation previously communicated from teacher to student is provided by programmed algorithms. There are two functions: (1) to instruct the client to generate proper descriptions of her fertility symptoms; and (2) to interpret the symptoms efficiently according to the Billings Method and to communicate the results to the client. The efficiency of billingsMentor was tested by using the historical records of students who were under the guidance of a teacher to emulate their experience under the guidance of billingsMentor. The results indicate that billingsMentor performs as well as the teacher/student in recognizing the peak of fertility but it is slightly less efficient than the teacher/student in establishing the basic infertile pattern. Advantages that arise from adapting natural family planning to information technology are discussed.

Implementing school-based cognitive behavior therapy for anxiety in students with autism or suspected autism via a train-the-trainer approach: Results from a clustered randomized trial.

LAY ABSTRACT: Autistic youth frequently experience anxiety that can negatively affect them at home, with friends, and at school. Autistic youth have difficulty accessing mental health care, and this is particularly true for youth from traditionally underserved backgrounds. Providing mental health programs in schools may increase access to care for autistic youth with anxiety. The purpose of the study was to train interdisciplinary school providers to deliver school-based Facing Your Fears, a cognitive behavior therapy program for anxiety in autistic youth. Seventy-seven interdisciplinary school providers across 25 elementary/middle schools were trained by their colleagues and members of the research (train-the-trainer approach). Eighty-one students with autism or suspected autism, ages 8-14 years, were randomly assigned to either school-based Facing Your Fears or usual care. Students in school-based Facing Your Fears showed significant reductions in anxiety compared to students in usual care according to caregiver and student report. Other measures involved examining change in provider cognitive behavior therapy knowledge after training and determining how well interdisciplinary school providers were able to deliver school-based Facing Your Fears. Results indicated that interdisciplinary school providers showed significant improvements in cognitive behavior therapy knowledge after training. Interdisciplinary school providers were able to deliver most of school-based Facing Your Fears activities and with good quality. The positive outcomes in this study are encouraging. Training interdisciplinary school providers to deliver school-based Facing Your Fears may increase access to care for anxious autistic students. Future directions and limitations are discussed.

TLR9 agonism differentially impacts human NK cell-mediated direct killing and antibody-dependent cell-mediated cytotoxicity.

There are two known mechanisms by which natural killer (NK) cells recognize and kill diseased targets: (i) direct killing and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated an indirect NK cell activation strategy for the enhancement of human NK cell killing function. We did this by leveraging the fact that toll-like receptor 9 (TLR9) agonism within pools of human peripheral blood mononuclear cells (PBMCs) results in a robust interferon signaling cascade that leads to NK cell activation. After TLR9 agonist stimulation, NK cells were enriched and incorporated into assays to assess their ability to kill tumor cell line targets. Notably, differential impacts of TLR9 agonism were observed-direct killing was enhanced while ADCC was not increased. To ensure that the observed differential effects were not attributable to differences between human donors, we recapitulated the observation using our Natural Killer-Simultaneous ADCC and Direct Killing Assay (NK-SADKA) that controls for human-to-human differences. Next, we observed a treatment-induced decrease in NK cell surface CD16-known to be shed by NK cells post-activation. Given the essential role of CD16 in ADCC, such shedding could account for the observed differential impact of TLR9 agonism on NK cell-mediated killing capacity.

Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects.

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli. SIGNIFICANCE: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL.

Delivery of a national prenatal exome sequencing service in England: a mixed methods study exploring healthcare professionals' views and experiences.

Introduction: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS. Methods: A survey (n = 159) and semi-structured interviews (n = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future. Results: Overall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions. Conclusion: Healthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals.

BET inhibition reforms the immune microenvironment and alleviates T cell dysfunction in chronic lymphocytic leukemia.

Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eµ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.

Virtual BUILD Research Collaboratory: A biomedical data science training using innovative pedagogy to address structures of racism and inequitable stress for undergraduates of color.

OBJECTIVE: The unprecedented events of 2020 required a pivot in scientific training to better prepare the biomedical research workforce to address global pandemics, structural racism, and social inequities that devastate human health individually and erode it collectively. Furthermore, this pivot had to be accomplished in the virtual environment given the nation-wide lockdown. METHODS: These needs and context led to leveraging of the San Francisco Building Infrastructure Leading to Diversity (SF BUILD) theories of change to innovate a Virtual BUILD Research Collaboratory (VBRC). The purpose of VBRC was to train Black, Indigenous, and people of color (BIPOC) students to apply their unique perspectives to biomedical research. These training activities were evaluated using a pre-post survey design that included both validated and new psychosocial scales. A new scale was piloted to measure culturally relevant pedagogy. RESULTS: VBRC scholars increased science identity on two items: thinking of myself as a scientist (+1point, p = 0.006) and belonging to a community of scientists (+1point, p = 0.069). Overall, scholars perceived stress also decreased over VBRC (-2.35 points, p = 0.02). Post VBRC, scholars had high agency scores (µ = 11.02, Md = 12, range = 6-12, σ = 1.62) and cultural humility scores (µ = 22.11, Md = 23, range = 12-24, σ = 2.71). No notable race/ethnic differences were found in any measures. CONCLUSIONS: Taken together, our innovative approach to data science training for BIPOC in unprecedented times shows promise for better preparing the workforce critically needed to address the fundamental gaps in knowledge at the intersection of public health, structural racism, and biomedical sciences.

Etiology of hospital mortality in children living in low- and middle-income countries: a systematic review and meta-analysis.

In 2019, 80% of the 7.4 million global child deaths occurred in low- and middle-income countries (LMICs). Global and regional estimates of cause of hospital death and admission in LMIC children are needed to guide global and local priority setting and resource allocation but are currently lacking. The study objective was to estimate global and regional prevalence for common causes of pediatric hospital mortality and admission in LMICs. We performed a systematic review and meta-analysis to identify LMIC observational studies published January 1, 2005-February 26, 2021. Eligible studies included: a general pediatric admission population, a cause of admission or death, and total admissions. We excluded studies with data before 2,000 or without a full text. Two authors independently screened and extracted data. We performed methodological assessment using domains adapted from the Quality in Prognosis Studies tool. Data were pooled using random-effects models where possible. We reported prevalence as a proportion of cause of death or admission per 1,000 admissions with 95% confidence intervals (95% CI). Our search identified 29,637 texts. After duplicate removal and screening, we analyzed 253 studies representing 21.8 million pediatric hospitalizations in 59 LMICs. All-cause pediatric hospital mortality was 4.1% [95% CI 3.4%-4.7%]. The most common causes of mortality (deaths/1,000 admissions) were infectious [12 (95% CI 9-14)]; respiratory [9 (95% CI 5-13)]; and gastrointestinal [9 (95% CI 6-11)]. Common causes of admission (cases/1,000 admissions) were respiratory [255 (95% CI 231-280)]; infectious [214 (95% CI 193-234)]; and gastrointestinal [166 (95% CI 143-190)]. We observed regional variation in estimates. Pediatric hospital mortality remains high in LMICs. Global child health efforts must include measures to reduce hospital mortality including basic emergency and critical care services tailored to the local disease burden. Resources are urgently needed to promote equity in child health research, support researchers, and collect high-quality data in LMICs to further guide priority setting and resource allocation.

Contribution of nitrate assimilation to the fitness of Pseudomonas syringae pv. syringae B728a on plants.

The ability of Pseudomonas syringae pv. syringae to use nitrate as a nitrogen source in culture and on leaves was assessed. Substantial amounts of leaf surface nitrate were detected directly and by use of a bioreporter of nitrate on bean plants grown with a variety of nitrogen sources. While a nitrate reductase mutant, P. syringae ΔnasB, exhibited greatly reduced growth in culture with nitrate as the sole nitrogen source, it exhibited population sizes similar to those of the wild-type strain on leaves. However, the growth of the ΔnasB mutant was much less than that of the wild-type strain when cultured in bean leaf washings supplemented with glucose, suggesting that P. syringae experiences primarily carbon-limited and only secondarily nitrogen-limited growth on bean leaves. Only a small proportion of the cells of a green fluorescent protein (GFP)-based P. syringae nitrate reductase bioreporter, LK2(pOTNas4), exhibited fluorescence on leaves. This suggests that only a subset of cells experience high nitrate levels or that nitrate assimilation is repressed by the presence of ammonium or other nitrogenous compounds in many leaf locations. While only a subpopulation of P. syringae consumes nitrate at a given time on the leaves, the ability of those cells to consume this resource would be strongly beneficial to those cells, especially in environments in which nitrate is the most abundant form of nitrogen.

Single-strand nicks induce homologous recombination with less toxicity than double-strand breaks using an AAV vector template.

Gene targeting by homologous recombination (HR) can be induced by double-strand breaks (DSBs), however these breaks can be toxic and potentially mutagenic. We investigated the I-AniI homing endonuclease engineered to produce only nicks, and found that nicks induce HR with both plasmid and adeno-associated virus (AAV) vector templates. The rates of nick-induced HR were lower than with DSBs (24-fold lower for plasmid transfection and 4- to 6-fold lower for AAV vector infection), but they still represented a significant increase over background (240- and 30-fold, respectively). We observed severe toxicity with the I-AniI 'cleavase', but no evidence of toxicity with the I-AniI 'nickase.' Additionally, the frequency of nickase-induced mutations at the I-AniI site was at least 150-fold lower than that induced by the cleavase. These results, and the observation that the surrounding sequence context of a target site affects nick-induced HR but not DSB-induced HR, strongly argue that nicks induce HR through a different mechanism than DSBs, allowing for gene correction without the toxicity and mutagenic activity of DSBs.

Effect of Co-occurring Psychiatric Disorders on Treatment of Children with Autism Spectrum Disorder and Anxiety.

Co-occurring psychiatric diagnoses are very common in individuals with ASD. Little is known about the effect that co-occurring psychiatric conditions may have on treatment response to CBT for children with ASD and anxiety. The present study examined the relationship between co-occurring psychiatric diagnoses and response to CBT for anxiety in ninety youth with ASD. Psychiatric complexity did not appear to differentially impact treatment response. A notable portion of youth with anxiety and externalizing disorders such as ADHD, no longer met criteria for those externalizing diagnoses following intervention. Results indicate that youth with ASD and anxiety present with complex psychiatric profiles and CBT for anxiety may positively affect co-occurring diagnoses. In addition, thorough and nuanced assessment of psychiatric symptoms in youth with ASD is needed to ensure the differentiation between diagnoses of anxiety and other co-occurring psychiatric symptoms.