Sensory pollutants alter bird phenology and fitness across a continent.

Expansion of anthropogenic noise and night lighting across our planet1,2 is of increasing conservation concern3-6. Despite growing knowledge of physiological and behavioural responses to these stimuli from single-species and local-scale studies, whether these pollutants affect fitness is less clear, as is how and why species vary in their sensitivity to these anthropic stressors. Here we leverage a large citizen science dataset paired with high-resolution noise and light data from across the contiguous United States to assess how these stimuli affect reproductive success in 142 bird species. We find responses to both sensory pollutants linked to the functional traits and habitat affiliations of species. For example, overall nest success was negatively correlated with noise among birds in closed environments. Species-specific changes in reproductive timing and hatching success in response to noise exposure were explained by vocalization frequency, nesting location and diet. Additionally, increased light-gathering ability of species' eyes was associated with stronger advancements in reproductive timing in response to light exposure, potentially creating phenological mismatches7. Unexpectedly, better light-gathering ability was linked to reduced clutch failure and increased overall nest success in response to light exposure, raising important questions about how responses to sensory pollutants counteract or exacerbate responses to other aspects of global change, such as climate warming. These findings demonstrate that anthropogenic noise and light can substantially affect breeding bird phenology and fitness, and underscore the need to consider sensory pollutants alongside traditional dimensions of the environment that typically inform biodiversity conservation.

NGLY1 deficiency: a prospective natural history study.

N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates other proteins. It is characterized by severe global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of transaminases, (hypo)alacrima and progressive, diffuse, length-dependent sensorimotor polyneuropathy. A prospective natural history study (NHS) was conducted to elucidate clinical features and disease course. Twenty-nine participants were enrolled (15 onsite, 14 remotely) and followed for up to 32 months, representing ~29% of the ~100 patients identified worldwide. Participants exhibited profound developmental delays, with almost all developmental quotients below 20 on the Mullen Scales of Early Learning, well below the normative score of 100. Increased difficulties with sitting and standing suggested decline in motor function over time. Most patients presented with (hypo)alacrima and reduced sweat response. Pediatric quality of life was poor except for emotional function. Language/communication and motor skill problems including hand use were reported by caregivers as the most bothersome symptoms. Levels of the substrate biomarker, GlcNAc-Asn (aspartylglucosamine; GNA), were consistently elevated in all participants over time, independent of age. Liver enzymes were elevated for some participants but improved especially in younger patients and did not reach levels indicating severe liver disease. Three participants died during the study period. Data from this NHS informs selection of endpoints and assessments for future clinical trials for NGLY1 deficiency interventions. Potential endpoints include GNA biomarker levels, neurocognitive assessments, autonomic and motor function (particularly hand use), (hypo)alacrima and quality of life.

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.

Apalutamide for High-Risk Localized Prostate Cancer Following Radical Prostatectomy (Apa-RP).

INTRODUCTION: Approximately 25 to 50% of patients with high-risk localized prostate cancer experience biochemical recurrence within 2 years of radical prostatectomy. The Apa-RP study (NCT04523207) investigated whether adjuvant apalutamide plus androgen deprivation therapy in high-risk patients who have undergone radical prostatectomy improved biochemical recurrence-free survival. METHODS: Apa-RP was a multicenter, open-label, single-arm, phase 2 study conducted in community urology practices in the United States. High-risk patients who had radical prostatectomy received 12 cycles of apalutamide (240 mg daily; 28-day cycles) plus androgen deprivation therapy. The primary endpoint was biochemical recurrence-free survival. Secondary endpoints included testosterone recovery (≥150 ng/dL) and safety. RESULTS: One hundred eight patients were enrolled; median age was 66.0 years (range 46.0-77.0). Median pre-operative prostate specific antigen and baseline testosterone were 7.6 ng/mL (range 2.2-62.7) and 340.0 ng/dL (range 43.0-939.0), respectively. The biochemical recurrence-free rate at 24 months (12 months after completion of planned therapy) was 100% (90% CI 93-100). Serum testosterone recovery rate (≥50 and ≥150 ng/dL) 12 months after treatment completion was 96% (95% CI 88-98) and 77% (95% CI 66-85), respectively. Overall, 107 (99%) patients experienced treatment-emergent adverse events, with 24 (22%) experiencing grade 3 to 4 events. CONCLUSIONS: In Apa-RP, BCR-free survival was 100% with 77% of patients having testosterone recovery (≥150 ng/dL) within 12 months of actual treatment completion and a manageable safety profile. These results provide proof of concept that treatment intensification with 12 cycles of apalutamide plus ADT could become an option for patients with high-risk localized prostate cancer who have undergone radical prostatectomy.

Neonatal epidermolysis bullosa: a clinical practice guideline.

DEBRA International is undertaking a long-term initiative to develop clinical practice guidelines (CPGs) for epidermolysis bullosa (EB), to -improve the clinical care of people living with EB. Current neonatal care is based on evidence, clinical expertise and trial and error, with collaboration between the EB specialist team, parent or carer and patient, and is dependent on the neonate's individual presentation and type of EB. Early intervention based on research and clinical practice is needed to establish a foundation of knowledge to guide international practitioners to create and improve standards of care and to be able to work effectively with those newly diagnosed with EB. This CPG was created by an international panel with expertise working with persons with EB. The CPG focuses on neonatal care using a systematic review methodology covering four key areas: (i) diagnosis and parental psychosocial support; (ii) hospital management: medical monitoring, wound care and pain; (iii) feeding and nutrition; and (iv) discharge planning and EB education. These four areas highlight the importance of a multidisciplinary team approach, to provide a patient-specific holistic care model that incorporates the needs and wishes of the parents and carers. The Hospital Implementation Tool included promotes transfer of theory to clinical practice.

Proactive case finding of alcohol-related liver disease in high-risk populations: A systematic review.

BACKGROUND: Alcohol-related liver disease (ARLD) is often diagnosed at a late stage when mortality is unacceptably high. Earlier identification of ARLD may lead to reduced alcohol intake, participation in hepatocellular carcinoma surveillance and reduction in liver-related morbidity and mortality. People with alcohol use disorder (AUD) are at highest risk of ARLD. The aim of this systematic review was to understand the yield of proactive screening for ARLD amongst high-risk groups. METHODS: Embase, Medline, Scopus and grey literature were searched for studies describing proactive assessment for alcohol-related liver disease in people with a history of alcohol excess or diagnosed AUD. Outcomes of interest were fibrosis and cirrhosis detection rates, clinical outcomes, portal hypertension evaluation, attendance at follow-up and cost-effectiveness. RESULTS: Fifteen studies were identified for inclusion from 1115 returned by the search. Four key settings for patient engagement were identified as inpatient addiction services, outpatient addiction services, general acute hospital admissions and community outreach. Of these, acute hospital admissions were the highest yield for cirrhosis at 10.8%-29.6% and community outreach the lowest was 1.2%-2.3%. CONCLUSIONS: Targeted fibrosis assessment of high-risk populations for ARLD is feasible to conduct and identifies a proportion of patients at risk of advanced liver disease. The highest yield is amongst inpatients admitted with AUD. Prospective work is needed to establish which are the most effective and acceptable screening methods and the impact on long-term outcomes.

CTCF: master weaver of the genome.

CTCF is a highly conserved zinc finger protein implicated in diverse regulatory functions, including transcriptional activation/repression, insulation, imprinting, and X chromosome inactivation. Here we re-evaluate data supporting these roles in the context of mechanistic insights provided by recent genome-wide studies and highlight evidence for CTCF-mediated intra- and interchromosomal contacts at several developmentally regulated genomic loci. These analyses support a primary role for CTCF in the global organization of chromatin architecture and suggest that CTCF may be a heritable component of an epigenetic system regulating the interplay between DNA methylation, higher-order chromatin structure, and lineage-specific gene expression.

The Utility of the Level of Personality Functioning Scale in Maternal Samples: A Brief Report.

Maternal personality plays a role in how a mother parents her children and adolescents. Current trait-based measures of personality are acceptable for use in maternal samples, but the presence or absence of given personality traits might not be enough to describe how personality relates to parenting. The Level of Personality Functioning Scale (LPFS) could serve as a solution, as it was designed to capture level of dysfunction in personality without being reliant on specific personality traits. Research, however, has yet to demonstrate the LPFS as a useful measure of personality in maternal samples, thus the goal of this study. A sample of 123 mothers reported on behavioral problems in their adolescent-aged children and their own personality using both a trait-based measure and the LPFS. Our data showed that maternal reports on the LPFS were associated with maternal perceptions of adolescent behavioral problems, in addition to being an acceptable measure of personality in our maternal sample. We also provide support for incremental validity of the LPFS in our sample, as the LPFS uniquely predicted maternal perceptions of adolescent behavioral problems even after controlling for maternal personality traits. Our results are discussed in light of the limitations of the extant work on maternal personality and add to the literature by demonstrating that the LPFS is an acceptable and ubiquitous measure of personality in maternal samples.

Serotype-specific transduction of canine joint tissue explants and cultured monolayers by self-complementary adeno-associated viral vectors.

A formal screening of self-complementary adeno-associated virus (scAAV) vector serotypes in canine joint tissues has not been performed to date. Selecting appropriate serotypes is crucial for successful treatment due to their varying levels of tissue tropism. The objective of this study is to identify the most optimal scAAV vector serotype that maximizes transduction efficiencies in canine cell monolayer cultures (chondrocytes, synoviocytes, and mesenchymal stem cells) and tissue explant cultures (cartilage and synovium). Transduction efficiencies of scAAV serotypes 1, 2, 2.5, 3, 4, 5, 6, 8, and 9 were evaluated in each culture type in three different vector concentrations by encoding a green fluorescent protein. It was found that scAAV2 and 2.5 showed the overall highest transduction efficiency among serotypes with dose-response. Since possible immune response against conventional AAV2 was previously reported in dogs, the chimeric scAAV2.5 may be more suitable to use. Evaluation of the safety and efficacy of the scAAV2.5 vector with an appropriate therapeutic gene in vivo is indicated.

BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.

Phenotypic signatures of urbanization? Resident, but not migratory, songbird eye size varies with urban-associated light pollution levels.

Urbanization now exposes large portions of the earth to sources of anthropogenic disturbance, driving rapid environmental change and producing novel environments. Changes in selective pressures as a result of urbanization are often associated with phenotypic divergence; however, the generality of phenotypic change remains unclear. In this study, we examined whether morphological phenotypes in two residential species (Carolina Wren [Thryothorus ludovicianus] and Northern Cardinal [Cardinalis cardinalis]) and two migratory species (Painted Bunting [Passerina ciris], and White-eyed Vireo [Vireo griseus]), differed between urban core and edge habitats in San Antonio, Texas, USA. More specifically, we examined whether urbanization, associated sensory pollution (light and noise) and brightness (open, bright areas cause by anthropogenic land use) influenced measures of avian body (mass and frame size) and lateral eye size. We found no differences in body size between urban core and edge habitats for all species except the Painted Bunting, in which core-urban individuals were smaller. Rather than a direct effect of urbanization, this was due to differences in age structure between habitats, with urban-core areas consisting of higher proportions of younger buntings which are, on average, smaller than older birds. Residential birds inhabiting urban-core areas had smaller eyes compared to their urban-edge counterparts, resulting from a negative association between eye size and light pollution and brightness across study sites; notably, we found no such association in the two migratory species. Our findings demonstrate how urbanization may indirectly influence phenotypes by altering population demographics and highlight the importance of accounting for age when assessing factors driving phenotypic change. We also provide some of the first evidence that birds may adapt to urban environments through changes in their eye morphology, demonstrating the need for future research into relationships among eye size, ambient light microenvironment use, and disassembly of avian communities as a result of urbanization.

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.

Remuneration and Recruitment of Study Participants for AD Cohort Studies From the General Public and From Minority Communities.

INTRODUCTION: Offering remuneration for participation in studies of aging and Alzheimer Disease (AD) may improve recruitment, particularly among minoritized and low-income groups. But remuneration may also raise ethical problems and reduce altruistic motivations for participation. METHODS: A nationally representative sample of Americans (N=2030) with large (N=500) Black and Hispanic oversamples was asked about willingness to participate in a longitudinal AD cohort study after random assignment of remuneration ($0, $50/visit, $100/visit). Respondents were then asked about their perceived burden, risks, and societal contribution from participation. RESULTS: An offer of remuneration increased willingness to participate, with no difference between $50 and $100. The increase was similar across racial, ethnic, and income groups. Remuneration did not affect perceived risks or altruistic benefits. Compensation caused Whites and Hispanics, but not Blacks, to lower the perceived burden. DISCUSSION: Modest levels of remuneration are likely to improve recruitment to AD research studies without causing collateral ethical or motivation problems. Remuneration does not differentially enhance minority recruitment.

Active cycle of breathing technique versus oscillating PEP therapy versus walking with huffing during an acute exacerbation of bronchiectasis: a randomised, controlled trial protocol.

BACKGROUND: Airway clearance techniques (ACTs) for individuals with bronchiectasis are routinely prescribed in clinical practice and recommended by international guidelines, especially during an acute exacerbation. However, there is limited evidence of the efficacy of these techniques during an exacerbation to improve sputum expectoration, health-related quality-of-life (HRQOL) or exercise tolerance. The primary aim of this study is to compare the effects of the active cycle of breathing technique (ACBT), oscillating positive expiratory pressure (O-PEP) therapy, and walking with huffing on sputum expectoration for adults hospitalised with an acute exacerbation of bronchiectasis. Secondary aims are to compare the effects of these interventions on HRQOL, health status, exacerbation rates and hospital admissions in a six-month period following hospital discharge. METHODS: This multi-centre randomised controlled trial will recruit adults with an acute exacerbation of bronchiectasis requiring hospital admission. Participants will be randomised to receive one of three interventions: ACBT, O-PEP therapy, and walking with huffing. Outcome measures including sputum volume during and 1-h post ACT session, and 24-h sputum, as well as health status, HRQOL and exercise capacity will be completed during inpatient stay on day 2 and day 6 of admission, and within 24 h of hospital discharge. Time to first exacerbation, and time to first hospitalisation will be monitored via monthly phone calls for six months post hospital discharge. Health status and HRQOL will be assessed after discharge at two and six months, and exercise capacity will be assessed at six months post hospital discharge. DISCUSSION: Despite recommendations regarding the importance of ACT for individuals with bronchiectasis during an acute exacerbation, there is a gap in the literature regarding effectiveness of ACT when undertaken by individuals in this clinical state. This study will add to the evidence base regarding the effectiveness of commonly implemented ACTs during a hospital admission with an exacerbation of bronchiectasis. Additionally, it will contribute to knowledge of the long term effects on important and patient-centred outcomes, including incidence of future exacerbations, and HRQOL, which has not been previously established. Trial registration Registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12621000428864).

Correction: yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development.

[This corrects the article DOI: 10.1371/journal.pgen.1008841.].

yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development.

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.

Setting the stage: Biopsychosocial predictors of early childhood externalizing behaviors.

Research has indicated that biological (self-regulation), psychological (temperament), and social (maternal parenting behaviors) factors predict childhood externalizing behaviors. Few studies, however, have evaluated psychological, biological, and social factors in conjunction as predictors of childhood externalizing behaviors. Further, limited research has examined whether these biopsychosocial predictors during infancy and toddlerhood predict the onset of externalizing behaviors in early childhood. The present study aimed to examine the longitudinal relations between biopsychosocial predictors of child externalizing behaviors. Children and their mothers (n = 410) participated when children were 5, 24, and 36 months old. Child self-regulation was assessed via baseline respiratory sinus arrhythmia (RSA) at age 5 months, and child psychology was measured via maternal report of effortful control at age 24 months. Additionally, maternal intrusiveness was assessed during a mother-child interaction at age 5 months. At 36 months, mothers reported on child externalizing behaviors. Longitudinal path modeling was used to examine the direct and indirect effects of maternal intrusiveness and child effortful control on child externalizing behavior, as well as whether these effects were conditional upon child baseline RSA. Results showed a significant indirect effect of maternal intrusiveness on externalizing behavior through effortful control, and this pathway was moderated by baseline RSA after controlling for orienting regulation at age 5 months. These results suggest that early childhood externalizing behaviors are jointly affected by biological, psychological, and social factors during toddlerhood.

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions.

BACKGROUND: Subanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment. METHODS: Thirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report. RESULTS: Twenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37-0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η p2 = 0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36). CONCLUSION: A short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier NCT01945047.

A Participant-Level Integrative Data Analysis of Differential Placebo Response for Suicidal Ideation and Nonsuicidal Depressive Symptoms in Clinical Trials of Intravenous Racemic Ketamine.

BACKGROUND: Clinical trials of intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as IV ketamine) have consistently reported rapid and substantial reductions in overall depressive symptoms compared with saline (inactive placebo) or midazolam (active placebo). The evidence for IV ketamine's specific effects on suicidal ideation is less clear, however. This study sought to examine whether differential placebo (saline or midazolam) response to overall depressive symptoms vs suicidal ideation may help explain these divergent findings. METHODS: Data for this participant-level integrative data analysis were drawn from 151 participants across 10 studies, and linear regression was used to examine the relationship between placebo response for suicidal ideation vs other depressive symptoms indexed from standard rating scales-specifically, depressed mood, anhedonia, anxiety, and guilt-over time. RESULTS: For participants receiving saline placebo (n = 46), greater placebo response was observed for suicidal ideation compared with other symptoms indexed from standard depression rating scales, except for anxiety. For those receiving midazolam placebo (n = 105), greater placebo response was observed for suicidal ideation compared with depressed mood or anhedonia, and no significant differences were observed when comparing suicidal ideation with anxiety or guilt. CONCLUSIONS: Taken together, the results provide preliminary evidence of a differential placebo response for suicidal ideation vs other depressive symptoms, while anxiety and suicidal ideation appear to produce similar placebo response profiles. These findings may help explain the more modest findings in clinical IV ketamine trials for suicidal ideation than overall depression.