Subungual melanoma with cartilaginous differentiation: Molecular insights.

Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.

Robotic versus Laparoscopic Liver Resection in Various Settings: An International Multicenter Propensity Score Matched Study of 10.075 Patients.

OBJECTIVE: The aim of this study was to compare the perioperative outcomes of robotic liver surgery (RLS) and laparoscopic liver surgery (LLS) in various settings. SUMMARY BACKGROUND DATA: Clear advantages of RLS over LLS have rarely been demonstrated, and the associated costs of robotic surgery are generally higher than those of laparoscopic surgery. Therefore, the exact role of the robotic approach in minimally invasive liver surgery remains to be defined. METHODS: In this international retrospective cohort study, the outcomes of patients who underwent RLS and LLS for all indications between 2009 and 2021 in 34 hepatobiliary referral centers were compared. Subgroup analyses were performed to compare both approaches across several types of procedures: minor resections in the anterolateral (2, 3, 4b, 5, and 6) or posterosuperior segments (1, 4a, 7, 8), and major resections (≥3 contiguous segments). Propensity score matching (PSM) was used to mitigate the influence of selection bias. The primary outcome was textbook outcome in liver surgery (TOLS), previously defined as the absence of intraoperative incidents ≥grade 2, postoperative bile leak ≥grade B, severe morbidity, readmission, and 90-day or in-hospital mortality with the presence of an R0 resection margin in case of malignancy. The absence of a prolonged length of stay was added to define TOLS+. RESULTS: Among the 10.075 included patients, 1.507 underwent RLS and 8.568 LLS. After PSM, both groups constituted 1.505 patients. RLS was associated with higher rates of TOLS (78.3% vs. 71.8%, P<0.001) and TOLS+ (55% vs. 50.4%, P=0.026), less Pringle usage (39.1% vs. 47.1%, P<0.001), blood loss (100 vs. 200 milliliters, P<0.001), transfusions (4.9% vs. 7.9%, P=0.003), conversions (2.7% vs 8.8%, P<0.001), overall morbidity (19.3% vs. 25.7%, P<0.001) and R0 resection margins (89.8% vs. 86%, P=0.015), but longer operative times (190 vs. 210 min, P=0.015). In the subgroups, RLS tended to have higher TOLS rates, compared to LLS, for minor resections in the posterosuperior segments (n=431 per group, 75.9% vs. 71.2%, P=0.184) and major resections (n=321 per group, 72.9% vs. 67.5%, P=0.086), although these differences did not reach statistical significance. CONCLUSIONS: While both producing excellent outcomes, RLS might facilitate slightly higher TOLS rates than LLS.

Community detection in the human connectome: Method types, differences and their impact on inference.

Community structure is a fundamental topological characteristic of optimally organized brain networks. Currently, there is no clear standard or systematic approach for selecting the most appropriate community detection method. Furthermore, the impact of method choice on the accuracy and robustness of estimated communities (and network modularity), as well as method-dependent relationships between network communities and cognitive and other individual measures, are not well understood. This study analyzed large datasets of real brain networks (estimated from resting-state fMRI from n $$ n $$ = 5251 pre/early adolescents in the adolescent brain cognitive development [ABCD] study), and n $$ n $$ = 5338 synthetic networks with heterogeneous, data-inspired topologies, with the goal to investigate and compare three classes of community detection methods: (i) modularity maximization-based (Newman and Louvain), (ii) probabilistic (Bayesian inference within the framework of stochastic block modeling (SBM)), and (iii) geometric (based on graph Ricci flow). Extensive comparisons between methods and their individual accuracy (relative to the ground truth in synthetic networks), and reliability (when applied to multiple fMRI runs from the same brains) suggest that the underlying brain network topology plays a critical role in the accuracy, reliability and agreement of community detection methods. Consistent method (dis)similarities, and their correlations with topological properties, were estimated across fMRI runs. Based on synthetic graphs, most methods performed similarly and had comparable high accuracy only in some topological regimes, specifically those corresponding to developed connectomes with at least quasi-optimal community organization. In contrast, in densely and/or weakly connected networks with difficult to detect communities, the methods yielded highly dissimilar results, with Bayesian inference within SBM having significantly higher accuracy compared to all others. Associations between method-specific modularity and demographic, anthropometric, physiological and cognitive parameters showed mostly method invariance but some method dependence as well. Although method sensitivity to different levels of community structure may in part explain method-dependent associations between modularity estimates and parameters of interest, method dependence also highlights potential issues of reliability and reproducibility. These findings suggest that a probabilistic approach, such as Bayesian inference in the framework of SBM, may provide consistently reliable estimates of community structure across network topologies. In addition, to maximize robustness of biological inferences, identified network communities and their cognitive, behavioral and other correlates should be confirmed with multiple reliable detection methods.

Reward Learning as a Potential Mechanism for Improvement in Schizophrenia Spectrum Disorders Following Cognitive Remediation: Protocol for a Clinical, Nonrandomized, Pre-Post Pilot Study.

BACKGROUND: Cognitive impairment is common with schizophrenia spectrum disorders. Cognitive remediation (CR) is effective in improving global cognition, but not all individuals benefit from this type of intervention. A better understanding of the potential mechanism of action of CR is needed. One proposed mechanism is reward learning (RL), the cognitive processes responsible for adapting behavior following positive or negative feedback. It is proposed that the structure of CR enhances RL and motivation to engage in increasingly challenging tasks, and this is a potential mechanism by which CR improves cognitive functioning in schizophrenia. OBJECTIVE: Our primary objective is to examine reward processing in individuals with schizophrenia before and after completing CR and to compare this with a group of matched clinical controls. We will assess whether RL mediates the relationship between CR and improved cognitive function and reduced negative symptoms. Potential differences in social RL and nonsocial RL in individuals with schizophrenia will also be investigated and compared with a healthy matched control group. METHODS: We propose a clinical, nonrandomized, pre-post pilot study comparing the impact of CR on RL and neurocognitive outcomes. The study will use a combination of objective and subjective measures to assess neurocognitive, psychiatric symptoms, and neurophysiological domains. A total of 40 individuals with schizophrenia spectrum disorders (aged 18-35 years) will receive 12 weeks of CR therapy (n=20) or treatment as usual (n=20). Reward processing will be evaluated using a reinforcement learning task with 2 conditions (social reward vs nonsocial reward) at baseline and the 12-week follow-up. Functional magnetic resonance imaging responses will be measured during this task. To validate the reinforcement learning task, RL will also be assessed in 20 healthy controls, matched for age, sex, and premorbid functioning. Mixed-factorial ANOVAs will be conducted to evaluate treatment group differences. For the functional magnetic resonance imaging analysis, computational modeling will allow the estimation of learning parameters at each point in time, during each task condition, for each participant. We will use a variational Bayesian framework to measure how learning occurred during the experimental task and the subprocesses that underlie this learning. Second-level group analyses will examine how learning in patients differs from that observed in control participants and how CR alters learning efficiency and the underlying neural activity. RESULTS: As of September 2023, this study has enrolled 15 participants in the CR group, 1 participant in the treatment-as-usual group, and 11 participants in the healthy control group. Recruitment is expected to be completed by September 2024. Data analysis is expected to be completed and published in early 2025. CONCLUSIONS: The results of this study will contribute to the knowledge of CR and RL processes in severe mental illness and the understanding of the systems that impact negative symptoms and cognitive impairments within this population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52505.

Psychological interventions for cancer-related post-traumatic stress disorder: narrative review.

AIMS AND METHOD: This narrative review updates the evidence base for cancer-related post-traumatic stress disorder (PTSD). Databases were searched in December 2021, and included EMBASE, Medline, PsycINFO and PubMed. Adults diagnosed with cancer who had symptoms of PTSD were included. RESULTS: The initial search identified 182 records, and 11 studies were included in the final review. Psychological interventions were varied, and cognitive-behavioural therapy and eye movement desensitisation and reprocessing were perceived to be most efficacious. The studies were also independently rated for methodological quality, which was found to be hugely variable. CLINICAL IMPLICATIONS: There remains a lack of high-quality intervention studies for PTSD in cancer, and there is a wide range of approaches to managing these conditions, with a large heterogeneity in the cancer populations examined and methodologies used. Specific studies designed with patient and public engagement and that tailor the PTSD intervention to particular cancer populations under investigation are required.

Incidence of Severe Adverse Drug Reactions to Ultrasound Enhancement Agents in a Contemporary Echocardiography Practice.

OBJECTIVES: Prior data indicate a very rare risk of serious adverse drug reaction (ADR) to ultrasound enhancement agents (UEAs). We sought to evaluate the frequency of ADR to UEA administration in contemporary practice. METHODS: We retrospectively reviewed 4 US health systems to characterize the frequency and severity of ADR to UEA. Adverse drug reactions were considered severe when cardiopulmonary involvement was present and critical when there was loss of consciousness, loss of pulse, or ST-segment elevation. Rates of isolated back pain and headache were derived from the Mayo Clinic Rochester stress echocardiography database where systematic prospective reporting of ADR was performed. RESULTS: Among 26,539 Definity and 11,579 Lumason administrations in the Mayo Clinic Rochester stress echocardiography database, isolated back pain or headache was more frequent with Definity (0.49% vs 0.04%, P < .0001) but less common with Definity infusion versus bolus (0.08% vs 0.53%, P = .007). Among all sites there were 201,834 Definity and 84,943 Lumason administrations. Severe and critical ADR were more frequent with Lumason than with Definity (0.0848% vs 0.0114% and 0.0330% vs 0.0010%, respectively; P < .001 for each). Among the 3 health systems with >2,000 Lumason administrations, the frequency of severe ADR with Lumason ranged from 0.0755% to 0.1093% and the frequency of critical ADR ranged from 0.0293% to 0.0525%. Severe ADR rates with Definity were stable over time but increased in more recent years with Lumason (P = .02). Patients with an ADR to Lumason since the beginning of 2021 were more likely to have received a COVID-19 vaccination compared with matched controls (88% vs 75%; P = .05) and more likely to have received Moderna than Pfizer-Biotech (71% vs 26%, P < .001). CONCLUSION: Severe and critical ADR, while rare, were more frequent with Lumason, and the frequency has increased in more recent years. Additional work is needed to better understand factors, including associations with recently developed mRNA vaccines, which may be contributing to the increased rates of ADR to UEA since 2021.

A Pineal Parenchymal Tumor of Intermediate Differentiation in an Octogenarian Contains a Rare KBTBD4 Insertion.

Pineal parenchymal tumors are rare central nervous system tumors that pose diagnostic challenges for surgical pathologists. Due to their paucity, their clinicopathologic features are still being defined. We report an 86-year-old woman with a remote history of breast lobular carcinoma who presented with a 2-month neurologic history that included gait instability, blurry vision, and headaches. Magnetic resonance imaging revealed a lobular, heterogeneously enhancing pineal region mass compressing the aqueduct of Sylvius. A biopsy performed concomitant with endoscopic third ventriculostomy consisted of small sheets of cells with eosinophilic to clear cytoplasm, multipolar processes, and ovoid nuclei with stippled chromatin. Whole exome sequencing revealed a small in-frame insertion (duplication) in exon 4 of KBTBD4 (c.931_939dup, p.P311_R313dup/ p.R313_M314insPRR), which has very recently been reported in 2 pineal parenchymal tumors of intermediate differentiation (PPTID). Additionally, variants of uncertain significance in CEBPA (c.863G > C, p.R288P) and MYC (c.655T > C, p.S219P) were identified. Although PPTID is considered a disease of young adulthood, review of 2 institutional cohorts of patients with pineal region tumors revealed that 25% of individuals with PPTID were over 65 years of age. In conclusion, PPTID should be considered in the differential diagnosis of pineal region tumors in older adults.

Acylation of glycerolipids in mycobacteria.

We report on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria, a classical one wherein the acylation of the sn-1 position of glycerol-3-phosphate (G3P) precedes that of sn-2 and another wherein acylations proceed in the reverse order. Two unique acyltransferases, PlsM and PlsB2, participate in both pathways and hold the key to the unusual positional distribution of acyl chains typifying mycobacterial glycerolipids wherein unsaturated substituents principally esterify position sn-1 and palmitoyl principally occupies position sn-2. While PlsM selectively transfers a palmitoyl chain to the sn-2 position of G3P and sn-1-lysophosphatidic acid (LPA), PlsB2 preferentially transfers a stearoyl or oleoyl chain to the sn-1 position of G3P and an oleyl chain to sn-2-LPA. PlsM is the first example of an sn-2 G3P acyltransferase outside the plant kingdom and PlsB2 the first example of a 2-acyl-G3P acyltransferase. Both enzymes are unique in their ability to catalyze acyl transfer to both G3P and LPA.

Post-Operative Care of the Cancer Patient: Emphasis on Functional Recovery, Rapid Rescue, and Survivorship.

A cancer diagnosis and its subsequent treatments are life-changing events, impacting the patient and their family. Treatment options available for cancer care are developing at pace, with more patients now able to achieve a cancer cure. This is achieved through the development of novel cancer treatments, surgery, and modern imaging, but also as a result of better understanding treatment/surgical trauma, rescue after complications, perioperative care, and innovative interventions like pre-habilitation, enhanced recovery, and enhanced post-operative care. With more patients living with and beyond cancer, the role of survivorship and quality of life after cancer treatment is gaining importance. The impact cancer treatments can have on patients vary, and the "scars" treatments leave are not always visible. To adequately support patients through their cancer journeys, we need to look past the short-term interactions they have with medical professionals and encourage them to consider their lives after cancer, which often is not a reflection of life before a cancer diagnosis.

Laparoscopic Right Hemihepatectomy after Future Liver Remnant Modulation: A Single Surgeon's Experience.

BACKGROUND: Laparoscopic right hemihepatectomy (L-RHH) is still considered a technically complex procedure, which should only be performed by experienced surgeons in specialized centers. Future liver remnant modulation (FLRM) strategies, including portal vein embolization (PVE), and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), might increase the surgical difficulty of L-RHH, due to the distortion of hepatic anatomy, periportal inflammation, and fibrosis. Therefore, this study aims to evaluate the safety and feasibility of L-RHH after FLRM, when compared with ex novo L-RHH. METHODS: All consecutive right hemihepatectomies performed by a single surgeon in the period between October 2007 and March 2023 were retrospectively analyzed. The patient characteristics and perioperative outcomes of L-RHH after FLRM and ex novo L-RHH were compared. RESULTS: A total of 59 patients were included in the analysis, of whom 33 underwent FLRM. Patients undergoing FLRM prior to L-RHH were most often male (93.9% vs. 42.3%, p < 0.001), had an ASA-score >2 (45.5% vs. 9.5%, p = 0.006), and underwent a two-stage hepatectomy (45.5% vs. 3.8% p < 0.001). L-RHH after FLRM was associated with longer operative time (median 360 vs. 300 min, p = 0.008) and Pringle duration (31 vs. 24 min, p = 0.011). Intraoperative blood loss, unfavorable intraoperative incidents, and conversion rates were similar in both groups. There were no significant differences in length of hospital stay and 30-day overall and severe morbidity rates. Radical resection margin (R0) and textbook outcome rates were equal. One patient who underwent an extended RHH in the FLRM group deceased within 90 days of surgery, due to post-hepatectomy liver failure. CONCLUSION: L-RHH after FLRM is more technically complex than L-RHH ex novo, as objectified by longer operative time and Pringle duration. Nevertheless, this procedure appears safe and feasible in experienced hands.

Examining the outcomes of the first one hundred residents in a community based residential rehabilitation unit for people affected by severe and persistent mental illness.

OBJECTIVE: Community-based residential rehabilitation for people experiencing severe and persistent mental illness (SPMI) is increasingly available as an alternative to psychiatric inpatient care. Understanding who accesses these services and their outcomes will inform the optimal allocation of limited public mental health resources. METHOD: This retrospective cohort study explored the outcomes of the first 100 consumers supported by a new Australian Community Care Unit (CCU). The primary outcome focus was acute mental health service use (emergency department presentations, acute mental health inpatient admission days), and secondary outcome foci were accommodation independence and substance use. RESULTS: When the 365 days before and after CCU support were compared, significant reductions in acute mental health bed days were observed (22 days, W = 3.373, p = .001); greater reductions were noted for those staying >182 days (31 days, W = 3.373, p = .001). Additionally, significant improvements in accommodation independence were found, (W = 3.373, p = .001). CONCLUSION: CCU consumers experienced reductions in acute mental health inpatient service use and improved accommodation independence. These observations are consistent with the intended functioning of the residential rehabilitation service.

The relaxation zone: Initial analysis of stress management services for university students.

Objective: We evaluated the Relaxation Zone (RZ), a room with "relaxation stations" designed to reduce stress in college students. Participants: Participants (N = 994) were enrolled during the 2019 calendar year. Most participants were female (62.8%), freshmen (59.3%), and African American (44.9%). Methods: Students visiting the RZ completed a brief pretest and posttest that measured self-reported stress. Results: Paired sample t-tests across class groups (e.g., freshman, sophomore) revealed a significant reduction in stress from pretest (Mpooled = 6.0) to posttest (Mpooled = 4.5), with medium to large effect sizes (Cohen's d ranging from 0.53 to 0.88) during their first visit. For students having at least two visits (N = 348), an exploratory dose-response analysis demonstrated that an optimal dose of self-guided relaxation ranged from two to eight visits. Conclusions: These findings provide initial evidence that programs like the RZ can reduce student stress within a few visits.

Connectivity between countries established by landbirds and raptors migrating along the African-Eurasian flyway.

The conservation of long-distance migratory birds requires coordination between the multiple countries connected by the movements of these species. The recent expansion of tracking studies is shedding new light on these movements, but much of this information is fragmented and inaccessible to conservation practitioners and policy makers. We synthesized current knowledge on the connectivity established between countries by landbirds and raptors migrating along the African-Eurasian flyway. We reviewed tracking studies to compile migration records for 1229 individual birds, from which we derived 544 migratory links, each link corresponding to a species' connection between a breeding country in Europe and a nonbreeding country in sub-Saharan Africa. We used these migratory links to analyze trends in knowledge over time and spatial patterns of connectivity per country (across species), per species (across countries), and at the flyway scale (across all countries and all species). The number of tracking studies available increased steadily since 2010 (particularly for landbirds), but the coverage of existing tracking data was highly incomplete. An average of 7.5% of migratory landbird species and 14.6% of raptor species were tracked per country. More data existed from central and western European countries, and it was biased toward larger bodied species. We provide species- and country-level syntheses of the migratory links we identified from the reviewed studies, involving 123 populations of 43 species, migrating between 28 European and 43 African countries. Several countries (e.g., Spain, Poland, Ethiopia, Democratic Republic of Congo) are strategic priorities for future tracking studies to complement existing data, particularly on landbirds. Despite the limitations in existing tracking data, our data and results can inform discussions under 2 key policy instruments at the flyway scale: the African-Eurasian Migratory Landbirds Action Plan and the Memorandum of Understanding on the Conservation of Migratory Birds of Prey in Africa and Eurasia.

Conectividad entre países establecida por aves terrestres y rapaces que migran a través del corredor aéreo africano-euroasiático Resumen La conservación de las aves que migran grandes distancias requiere de una coordinación entre los varios países conectados por los movimientos de estas especies. La expansión reciente de los estudios de rastreo está descubriendo novedades en estos movimientos, aunque gran parte de esta información está fragmentada y es inaccesible para quienes practican y elaboran las políticas de conservación. Sintetizamos el conocimiento actual sobre la conectividad establecida entre países por las aves terrestres y rapaces que migran a través del corredor aéreo africano-euroasiático. Revisamos los estudios de rastreo para compilar los registros migratorios de 1229 aves, de los cuales derivamos 544 conexiones migratorias, con cada conexión correspondiendo a la conexión que tiene una especie entre un país europeo en donde se reproduce con un país de la África subsahariana en donde no se reproduce. Usamos estas conexiones migratorias para analizar las tendencias informativas en patrones espaciales y temporales de conectividad por país (en todas las especies), por especie (en todos los países) y a escala del corredor aéreo (en todas las especies y en todos los países). El número de estudios de rastreo disponibles incrementó gradualmente a partir de 2010 (particularmente para las aves terrestres), pero la cobertura de los datos de rastreo existentes estaba incompleta. Se rastreó en promedio 7.5% de especies de aves terrestres migratorias y 14.6% de aves rapaces por país. Existían más datos de los países del centro y oeste de Europa, los cuales estaban sesgados hacia las especies de mayor tamaño. Proporcionamos varias síntesis a nivel de especie y país de las conexiones migratorias que identificamos a partir de la revisión de estudios, las cuales involucran a 123 poblaciones de 43 especies que migran entre 28 países europeos y 43 países africanos. Varios países, como España, Polonia, Etiopía y la República Democrática del Congo son prioridades estratégicas para complementar los datos existentes en los siguientes estudios de rastreo, en especial para las aves terrestres. A pesar de las limitaciones que tienen los datos de rastreo existentes, nuestros datos y resultados pueden orientar las discusiones con dos instrumentos claves para las políticas: el Plan de Acción de las Aves Terrestres Migratorias Africanas-Euroasiáticas y el Memorando de Entendimiento sobre la Conservación de las Aves Rapaces Migratorias de África y Eurasia.

Relations between bedtime parenting behaviors and temperament across 14 cultures.

Objectives: The present study examined parental sleep-supporting practices during toddlerhood in relation to temperament across 14 cultures. We hypothesized that passive sleep-supporting techniques (e.g., talking, cuddling), but not active techniques (e.g., walking, doing an activity together), would be associated with less challenging temperament profiles: higher Surgency (SUR) and Effortful Control (EC) and lower Negative Emotionality (NE), with fine-grained dimensions exhibiting relationships consistent with their overarching factors (e.g., parallel passive sleep-supporting approach effects for dimensions of NE). Methods: Caregivers (N = 841) across 14 cultures (M = 61 families per site) reported toddler (between 17 and 40 months of age; 52% male) temperament and sleep-supporting activities. Utilizing linear multilevel regression models and group-mean centering procedures, we assessed the role of between- and within-cultural variance in sleep-supporting practices in relation to temperament. Results: Both within-and between-culture differences in passive sleep-supporting techniques were associated with temperament attributes, (e.g., lower NE at the between-culture level; higher within-culture EC). For active techniques only within-culture effects were significant (e.g., demonstrating a positive association with NE). Adding sleep-supporting behaviors to the regression models accounted for significantly more between-culture temperament variance than child age and gender alone. Conclusion: Hypotheses were largely supported. Findings suggest parental sleep practices could be potential targets for interventions to mitigate risk posed by challenging temperament profiles (e.g., reducing active techniques that are associated with greater distress proneness and NE).

Single Nucleotide Polymorphism (SNP) Arrays and Their Sensitivity for Detection of Genetic Changes in Human Pluripotent Stem Cell Cultures.

Human pluripotent stem cells (hPSCs) can be grown in culture indefinitely, making them a valuable tool for use in basic biology, disease modeling, and regenerative medicine. However, over prolonged periods in culture, hPSCs tend to acquire genomic aberrations that confer growth advantages, similar to those seen in some cancers. Monitoring the genomic stability of cultured hPSCs is critical to ensuring their efficacy and safety as a therapeutic tool. Most commonly employed methods for monitoring of hPSC genomes are cytogenetic methods, such as G-banding. Nonetheless, such methods have limited resolution and sensitivity for detecting mosaicism. Single nucleotide polymorphism (SNP) array platforms are a potential alternative that could improve detection of abnormalities. Here, we outline protocols for SNP array whole-genome screening of hPSCs. Moreover, we detail the procedure for assessing the SNP array's sensitivity in detecting low-level mosaic copy-number changes. We show that mosaicism can be confidently identified in samples only once they contain 20% variants, although samples containing 10% variants typically display enough variation to warrant further investigation and confirmation, for example by using a more sensitive targeted method. Finally, we highlight the advantages and limitations of SNP arrays, including a cost comparison of SNP arrays versus other commonly employed methods for detection of genetic changes in hPSC cultures. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: DNA sample preparation for SNP arrays Basic Protocol 2: SNP array hybridization, washing, and scanning Basic Protocol 3: SNP array data analysis Support Protocol: Assessment of SNP array sensitivity for detection of mosaicism.

A Randomized Control Trial of Cognitive Compensatory Training (CCT) and Computerized Interactive Remediation of Cognition-Training for Schizophrenia (CIRCuiTS).

Background: Various modes of delivering cognitive remediation (CR) are effective, but there have been few head-to-head trials of different approaches. This trial aimed to evaluate the relative effectiveness of two different programmes, Cognitive Compensatory Training (CCT) and Computerized Interactive Remediation of Cognition-Training for Schizophrenia (CIRCuiTs). Methods: The study used a single-blind randomized, controlled trial to examine the efficacy and effectiveness of the two therapies. The study aimed to enroll 100 clinically stable patients between the ages of 18 and 65 years who had been diagnosed with a schizophrenia spectrum disorder. Participants were randomized to either the CCT or CIRCuiTs therapy groups. The primary outcome measures were neurocognition using the Brief Assessment of Cognition Scale (BACS) and the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS). The secondary measure was functional outcomes using the Social Functioning Scale (SFS). Results: There was no group difference in any of the outcome measures post-intervention or at follow-up. Both groups had a small improvement on their SSTICS scores between baseline (M = 30.52 and SD = 14.61) and post-intervention (M = 23.96 and SD = 10.92). Verbal memory scores as measured by list learning improved for both groups between baseline (z = -1.62) and 3-month follow-up (z = -1.03). Both groups improved on the token motor task between baseline (z = -1.38) and post-intervention (z = -0.69). Both groups had a decline in Symbol Coding scores between baseline (z = 0.05) and 3-month follow-up (z = -0.82). Discussion: This underpowered study found no difference in effect between the two approaches studied. If future studies confirm this finding, then it has implications for services where cost and lack of computer technology could pose a barrier in addressing the cognitive domain of schizophrenia spectrum disorders. The final sample size compromised the power of the study to conclusively determine a significant effect.

2-Aminoimidazoles Inhibit Mycobacterium abscessus Biofilms in a Zinc-Dependent Manner.

Biofilm growth is thought to be a significant obstacle to the successful treatment of Mycobacterium abscessus infections. A search for agents capable of inhibiting M. abscessus biofilms led to our interest in 2-aminoimidazoles and related scaffolds, which have proven to display antibiofilm properties against a number of Gram-negative and Gram-positive bacteria, including Mycobacterium tuberculosis and Mycobacterium smegmatis. The screening of a library of 30 compounds led to the identification of a compound, AB-2-29, which inhibits the formation of M. abscessus biofilms with an IC50 (the concentration required to inhibit 50% of biofilm formation) in the range of 12.5 to 25 µM. Interestingly, AB-2-29 appears to chelate zinc, and its antibiofilm activity is potentiated by the addition of zinc to the culture medium. Preliminary mechanistic studies indicate that AB-2-29 acts through a distinct mechanism from those reported to date for 2-aminoimidazole compounds.

Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus.

A search for alternative Mycobacterium abscessus treatments led to our interest in the two-component regulator DosRS, which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity of antibiotics used in combination. The identification of antimalarial drugs as potent inhibitors and adjunct inhibitors of M. abscessus in vivo offers repurposing opportunities that could have an immediate impact in the clinic.