Effects of a bioengineered allogeneic cellular construct on burn-related macrophage phenotype.

Bioengineered allogeneic cellularised constructs (BACC) exert pro-healing effects in burn wounds and skew macrophage phenotype towards a predominately reparative phenotype. However, whether BACC can modulate the phenotype of dysregulated macrophages, like those present in burn wounds, is not known. To better understand the macrophage modulatory characteristics of the BACC, primary human macrophages were polarised to the M2b phenotype, an immunosuppressive phenotype relevant to burn wounds, by simultaneously exposing macrophages to polystyrene plate-coated immunoglobulin G and the endotoxin lipopolysaccharide (LPS). The resulting macrophage phenotype upregulated both inflammatory and reparative genes, and increased secretion of the M2b marker CCL1 compared to five different in vitro macrophage phenotypes. M2b macrophages were cultured with the BACC in the presence or absence of LPS to mimic infection, which is a common occurrence in burn wounds. The BACC caused up-regulation of reparative gene sets and down-regulation of pro-inflammatory gene sets, even when LPS was present in the cell culture media. Co-cultures were maintained for 1, 3, or 5 days in the presence of LPS, and by day 1 both non-activated macrophages and M2b macrophages exhibited signs of endotoxin tolerance, as demonstrated by a reduced secretion of tumour necrosis factor α (TNFα) in response to fresh LPS stimulus. The BACC was not able to prevent endotoxin tolerance, but reparative genes were upregulated in macrophages chronically exposed to LPS. These results suggest that the BACC can promote a reparative phenotype in dysregulated macrophages relevant to the pathophysiology of burns.

Education Research: Establishing a Postgraduate Year-1 Director Enhances Well-Being for Adult Neurology Residents.

Background and Objectives: Adult neurology clinical trainees in Accreditation Council for Graduate Medical Education (ACGME)-accredited residency programs spend their postgraduate year (PGY)-1 within the internal medicine department, potentially causing a perceived disconnect with their neurology program. Our Adult Neurology Clinical Competency Committee found this disconnect may decrease resident well-being. We hypothesized implementing a novel PGY-1 Director role focusing on unique aspects of this first year would improve resident well-being and connection to the neurology program. Methods: The PGY-1 Director was established as an associate program director in the adult neurology residency program with goals to improve wellness, advocacy, compliance with ACGME requirements, education, and communication. Anonymous surveys compared preintervention (before the PGY-1 Director role) with postintervention resident opinions on PGY-1 experience, assessing wellness, burnout, and perception of advocacy. Results: A total of 15 (75%) preintervention residents and 23 (96%) postintervention residents completed the study surveys. 53.7% of preintervention residents agreed or strongly agreed to feeling burned out, while only 17.4% of postintervention residents agreed they felt burned out and none strongly agreed. Significant improvement occurred in feeling supported clinically and emotionally and feeling validated. Most postintervention residents felt the PGY-1 Director was valuable and directly led to positive change. The relationship between the neurology and internal medicine departments was improved. Discussion: A dedicated PGY-1 Director position can improve trainee wellness outcomes and relationships between preliminary and matched departments. This mutually benefits both programs but requires substantial resources. We propose this as a best practice when feasible for ACGME programs with the following suggestions: (1) provide dedicated full-time equivalent time, (2) meet with preliminary program leadership regularly, (3) meet with PGY-1 trainees during orientation and at least quarterly, (4) serve as an advocate, and (5) facilitate mentorship in areas of interest.

Fear of Cancer Recurrence in Adult Survivors of Childhood Cancer.

Importance: Fear of cancer recurrence is common among survivors of adult-onset cancer and associated with increased distress, functional impairment, and health care utilization. However, little is known about the prevalence and risk factors of fear of cancer recurrence among adult survivors of childhood cancer who are also at high risk for subsequent malignant neoplasms. Objective: To characterize the prevalence of and risk factors for clinically significant fear of cancer recurrence in adult survivors of childhood cancer. Design, Setting, and Participants: This cross-sectional investigation included participants recruited from the Childhood Cancer Survivor Study, a retrospective cohort study of long-term childhood cancer survivors treated at 31 institutions between 1970 and 1999 across North America. Participants were recruited and completed psychosocial measures via online survey between October 2018 and April 2019. Cancer and treatment-related variables were abstracted from medical records. Data were analyzed from May 2023 to July 2024. Main Outcomes and Measures: Clinically significant fear of cancer recurrence was assessed via the Fear of Cancer Recurrence Inventory-Short Form. Poisson regression models estimated prevalence ratios (PRs) with 95% CIs adjusted for age and sex to examine the associations of demographic, disease, treatment, and psychosocial variables with fear of cancer recurrence. Results: The final sample included 229 adult survivors of childhood cancer (115 female [50.2%]; mean [SD] age, 39.6 [9.9] years; mean [SD] time since diagnosis, 31.7 [8.4] years). Among survivors, 38 (16.6%; 95% CI, 11.6%-21.6%) reported clinically significant fear of cancer recurrence, and an additional 36 (15.7%) reported high fear of cancer recurrence. Clinically significant fear of cancer recurrence was associated with unemployment (PR, 2.5; 95% CI, 1.3-4.8), presence of neurologic chronic health conditions (PR, 3.3; 95% CI, 1.8-6.1), treatment with pelvic radiation (PR, 2.9; 95% CI, 1.5-5.6), and amputation or limb sparing surgery (PR, 2.4; 95% CI, 1.2-4.9). Higher risk of clinically significant fear of cancer recurrence was also associated with having either elevated anxiety or depression (PR, 2.6; 95% CI, 1.2-5.9), having both elevated (PR, 3.2; 95% CI, 1.2-8.4), and perceived poor health status (PR, 3.0; 95% CI, 3.1-9.7). Conclusions and Relevance: Decades following treatment, one-third of childhood cancer survivors in this study reported elevated fear their cancer will recur or a subsequent malignant neoplasm will develop. Findings suggest that fear of cancer recurrence should be routinely screened, and clinically significant symptoms intervened upon as a part of survivorship care.

GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia.

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.

Building a machine learning-assisted echocardiography prediction tool for children at risk for cancer therapy-related cardiomyopathy.

BACKGROUND: Despite routine echocardiographic surveillance for childhood cancer survivors, the ability to predict cardiomyopathy risk in individual patients is limited. We explored the feasibility and optimal processes for machine learning-enhanced cardiomyopathy prediction in survivors using serial echocardiograms from five centers. METHODS: We designed a series of deep convolutional neural networks (DCNNs) for prediction of cardiomyopathy (shortening fraction ≤ 28% or ejection fraction ≤ 50% on two occasions) for at-risk survivors ≥ 1-year post initial cancer therapy. We built DCNNs with four subsets of echocardiographic data differing in timing relative to case (survivor who developed cardiomyopathy) index diagnosis and two input formats (montages) with differing image selections. We used holdout subsets in a 10-fold cross-validation framework and standard metrics to assess model performance (e.g., F1-score, area under the precision-recall curve [AUPRC]). Performance of the input formats was compared using a combined 5 × 2 cross-validation F-test. RESULTS: The dataset included 542 pairs of montages: 171 montage pairs from 45 cases at time of cardiomyopathy diagnosis or pre-diagnosis and 371 pairs from 70 at-risk survivors who didn't develop cardiomyopathy during follow-up (non-case). The DCNN trained to distinguish between non-case and time of cardiomyopathy diagnosis or pre-diagnosis case montages achieved an AUROC of 0.89 ± 0.02, AUPRC 0.83 ± 0.03, and F1-score: 0.76 ± 0.04. When limited to smaller subsets of case data (e.g., ≥ 1 or 2 years pre-diagnosis), performance worsened. Model input format did not impact performance accuracy across models. CONCLUSIONS: This methodology is a promising first step toward development of a DCNN capable of accurately differentiating pre-diagnosis versus non-case echocardiograms to predict survivors more likely to develop cardiomyopathy.

Clinical guidance for cannabidiol-associated hepatotoxicity: A narrative review.

There is increasing evidence that cannabidiol (CBD) use is associated with clinically significant liver enzyme (LE) elevations and drug-induced liver injury (DILI). The proportion of LE elevations and DILI events reported in the literature meet the Council for International Organizations of Medical Sciences' (CIOMS) classification of a common adverse drug reaction. However, these potential adverse events are unknown to many clinicians and may be overlooked. The increasing use of CBD for both medical and non-medical use necessitates clear direction in the diagnosis and management of CBD-associated hepatotoxicity. To our knowledge, no such clinical guidance currently exists. For people presenting with elevated LEs, CBD use should be screened for and be considered in the differential diagnosis. This narrative review will provide clinicians with guidance in the prevention, detection, and management of CBD-related hepatotoxicity.

GHSR blockade, but not reduction of peripherally circulating ghrelin via ß1-adrenergic receptor antagonism, decreases binge-like alcohol drinking in mice.

Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. The stomach-derived peptide ghrelin, and its receptor, the growth hormone secretagogue receptor (GHSR), both of which are expressed in the brain and periphery, are implicated in alcohol-related outcomes. We previously found that systemic and central administration of GHSR antagonists reduced binge-like alcohol drinking, whereas a ghrelin vaccine did not. Thus, we hypothesized that central GHSR drives binge-like alcohol drinking independently of peripheral ghrelin. To investigate this hypothesis, we antagonized ß1-adrenergic receptors (ß1ARs), which are required for peripheral ghrelin release, and combined them with GHSR blockers. We found that both systemic ß1AR antagonism with atenolol (peripherally restricted) and metoprolol (brain permeable) robustly decreased plasma ghrelin levels. Also, ICV administration of atenolol had no effect on peripheral endogenous ghrelin levels. However, only metoprolol, but not atenolol, decreased binge-like alcohol drinking. The ß1AR antagonism also did not prevent the effects of the GHSR blockers JMV2959 and PF-5190457 in decreasing binge-like alcohol drinking. These results suggest that the GHSR rather than peripheral endogenous ghrelin is involved in binge-like alcohol drinking. Thus, GHSRs and ß1ARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems.

Aqueous extractable nonfibrillar and sarkosyl extractable fibrillar Alzheimer's disease tau seeds have distinct properties.

Pathological tau fibrils in progressive supranuclear palsy, frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer's disease each have unique conformations, and post-translational modifications that correlate with unique disease characteristics. However, within Alzheimer's disease (AD), both fibrillar (sarkosyl insoluble (AD SARK tau)), and nonfibrillar (aqueous extractable high molecular weight (AD HMW tau)) preparations have been suggested to be seed-competent. We now explore if these preparations are similar or distinct in their in vivo seeding characteristics. Using an in vivo amplification and time-course paradigm we demonstrate that, for AD HMW and AD SARK tau species, the amplified material is biochemically similar to the original sample. The HMW and SARK materials also show different clearance, propagation kinetics, and propagation patterns. These data indicate the surprising co-occurrence of multiple distinct tau species within the same AD brain, supporting the idea that multiple tau conformers - both fibrillar and nonfibrillar- can impact phenotype in AD.

Cognitive resilience to Alzheimer's disease characterized by cell-type abundance.

INTRODUCTION: The molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood. METHODS: Abundance of 13 cell types and neuronal subtypes in brain bulk RNA-seq data from the anterior caudate, dorsolateral prefrontal cortex (DLPFC), and posterior cingulate cortex (PCC) obtained from 434 AD cases, 318 cognitively resilient AD cases, and 188 controls in the Religious Orders Study and Rush Memory and Aging Project was estimated by deconvolution. RESULTS: PVALB+ neuron abundance was negatively associated with cognitive status and tau pathology in the DLPFC and PCC (Padj < 0.001) and the most reduced neuronal subtype in AD cases compared to controls in DLPFC (Padj = 8.4 × 10-7) and PCC (Padj = 0.0015). We identified genome-wide significant association of neuron abundance with TMEM106B single nucleotide polymorphism rs13237518 in PCC (p = 6.08 × 10-12). rs13237518 was also associated with amyloid beta (p = 0.0085) and tangles (p = 0.0073). DISCUSSION: High abundance of PVALB+ neurons may be a marker of CR. TMEM106B variants may influence CR independent of AD pathology. HIGHLIGHTS: Neuron retention and a lack of astrocytosis are highly predictive of Alzheimer's disease (AD) resilience. PVALB+ GABAergic and RORB+ glutamatergic neurons are associated with cognitive status. A TMEM106B single nucleotide polymorphism is related to lower AD risk, higher neuron count, and increased AD pathology.

Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI.

There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT2A receptors. Restoration of 5-HT2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior.

Adrenergic C1 neurons enhance anxiety via projections to PAG.

Anxiety is an emotional state precipitated by the anticipation of real or potential threats. Anxiety disorders are the most prevalent psychiatric illnesses globally and increase the risk of developing comorbid conditions that negatively impact the brain and body. The etiology of anxiety disorders remains unresolved, limiting improvement of therapeutic strategies to alleviate anxiety-related symptoms with increased specificity and efficacy. Here, we applied novel intersectional tools to identify a discrete population of brainstem adrenergic neurons, named C1 cells, that promote aversion and anxiety-related behaviors via projections to the periaqueductal gray matter (PAG). While C1 cells have traditionally been implicated in modulation of autonomic processes, rabies tracing revealed that they receive input from brain areas with diverse functions. Calcium-based in vivo imaging showed that activation of C1 cells enhances excitatory responses in vlPAG, activity that is exacerbated in times of heightened stress. Furthermore, inhibition of C1 cells impedes the development of anxiety-like behaviors in response to stressful situations. Overall, these findings suggest that C1 neurons are positioned to integrate complex information from the brain and periphery for the promotion of anxiety-like behaviors.

Using Vaccine Safety Data to Demonstrate the Potential of Pooled Data Analysis.

In Canada, vaccine safety studies are often conducted at the provincial/territorial level where the primary data on vaccination reside. Combining health services data from multiple jurisdictions using a pooled data analytic approach would reduce the amount of time needed to detect vaccine safety signals. To determine the difference in the time it would take to identify safety signals using different proportions of the Canadian population, we conducted power and sample size calculations for a hypothetical self-controlled case series-based surveillance analysis. We used scenarios modeled after the real-world examples of myocarditis and vaccine-induced immune thrombotic thrombocytopenia (VITT) following COVID-19 vaccination as our base cases. Our calculations demonstrated that in the case of a myocarditis-type event, a pooled analysis would reduce the time needed to detect a safety signal by over 60% compared to using Ontario data alone. In the case of a VITT-type event, a pooled analysis could detect a safety signal 49 days sooner than using Ontario data alone, potentially averting as many as 30 events. Our analysis demonstrates that there is substantial value in using pan-Canadian health services data to evaluate the safety of vaccines. Efforts should be made to develop a pan-Canadian vaccine data source to allow for an earlier evaluation of suspected adverse events following immunization.

What Is Childhood Lymphoma?

This JAMA Pediatrics Patient Page describes the symptoms, diagnosis, and treatment of childhood lymphoma.

Enhancing genetic association power in endometriosis through unsupervised clustering of clinical subtypes identified from electronic health records.

Endometriosis is a complex and heterogeneous condition affecting 10% of reproductive-age women, and yet, it often goes undiagnosed for several years. Limited observed heritability (7%) of large genetic association studies may be attributable to underlying heterogeneity of disease mechanisms. Therefore, we conducted this study to investigate genetic associations across sub-phenotypes of endometriosis. We performed unsupervised clustering of 4,078 women with endometriosis based on known endometriosis risk factors, symptoms, and concomitant conditions. The clusters were characterized by examining electronic health record (EHR) data and comprehensive chart reviews. We then performed genetic association for each cluster with 39 endometriosis-associated loci (Total Nendometriosis cases = 12,350). We identified five sub-phenotype clusters: (1) pain comorbidities, (2) uterine disorders, (3) pregnancy complications, (4) cardiometabolic comorbidities, and (5) HER-asymptomatic. Bonferroni significant loci included PDLIM5 for the cluster 1, GREB1 for cluster 2, WNT4 for cluster 3, RNLS for cluster 4, and ABO for cluster 5. The difference in associations between the groups suggests complex and varied genetic mechanisms of endometriosis and its symptoms. This study enhances our understanding of the clinical patterns of endometriosis sub-phenotypes, showcasing the innovative approach employed to investigate this complex disease.

Usability of a Web-Based App for Increasing Adolescent Vaccination in Primary Care Settings: Think-Aloud and Survey Assessment.

BACKGROUND: In the United States, only 58% of teens receive the recommended 2 doses of the human papillomavirus vaccine by 15 years of age. Overcoming vaccine hesitancy often requires effective communication between clinicians and parents to address specific concerns. To support this, we developed ProtectMe4, a multilevel, theory-informed web-based intervention designed to address parents' vaccine-related questions and assist clinicians in discussing vaccine concerns for 4 adolescent vaccines. OBJECTIVE: This study aims to evaluate the usability of ProtectMe4 in routine care settings across 3 pediatric primary care clinics. Specifically, the study aims to (1) observe the proposed workflow in practice, (2) identify usability issues experienced by parents and clinicians, and (3) assess the perceptions of both parents and clinicians regarding the app's usability. METHODS: On designated days in 2020 and 2021, the study team recruited parents of 11- to 12-year-old patients attending appointments with participating clinicians. We conducted think-aloud assessments during routine care visits and administered a usability survey after participants used the app. For parents, we simultaneously video-recorded the app screens and audio-recorded their commentary. For clinicians, observational notes were taken regarding their actions and comments. Timings recorded within the app provided data on the length of use. We reviewed the recordings and notes to compile a list of identified issues and calculated the frequencies of survey responses. RESULTS: Out of 12 parents invited to use the app, 9 (75%) participated. Two parents who were invited outside of the planned workflow, after seeing the clinician, refused to participate. For the parents whose child's vaccination record was identified by the app, the median time spent using the app was 9 (range 6-28) minutes. Think-aloud assessment results for parents were categorized into 2 themes: (1) troubleshooting vaccine record identification and (2) clarifying the app content and purpose. Among the 8 parents who completed the survey, at least 75% (6/8) agreed with each acceptability measure related to user satisfaction, perceived usefulness, and acceptance. These parents' children were patients of 4 of the 7 participating clinicians. Consistent with the planned workflow, clinicians viewed the app before seeing the patient in 4 of 9 (44%) instances. The median time spent on the app per patient was 95 (range 5-240) seconds. Think-aloud assessment results for clinicians were grouped into 2 themes: (1) trust of app vaccine results and (2) clarifying the app content. On the survey, clinicians were unanimously positive about the app, with an average System Usability Scale score of 87.5 (SE 2.5). CONCLUSIONS: This mixed methods evaluation demonstrated that ProtectMe4 was usable and acceptable to both parents and clinicians in real-world pediatric primary care. Improved coordination among clinic staff is needed to ensure the app is consistently offered to patients and reviewed by clinicians before seeing the patient.

Key roles of C2/GAP domains in SYNGAP1-related pathophysiology.

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency. However, some affected individuals carry missense mutations in its calcium/lipid binding (C2) and GAP domains, suggesting that many clinical features result from loss of functions carried out by these domains. To test this hypothesis, we targeted the exons encoding the C2 and GAP domains of SYNGAP. Rats heterozygous for this deletion exhibit reduced exploration and fear extinction, altered social investigation, and spontaneous seizures-key phenotypes shared with Syngap heterozygous null rats. Together, these findings indicate that the reduction of SYNGAP C2/GAP domain function is a main feature of SYNGAP haploinsufficiency. This rat model provides an important system for the study of ID, autism, and epilepsy.

Latest Developments in "Adaptive Enrichment" Clinical Trial Designs in Oncology.

As cancer has become better understood on the molecular level with the evolution of gene sequencing techniques, considerations for individualized therapy using predictive biomarkers (those associated with a treatment's effect) have shifted to a new level. In the last decade or so, randomized "adaptive enrichment" clinical trials have become increasingly utilized to strike a balance between enrolling all patients with a given tumor type, versus enrolling only a subpopulation whose tumors are defined by a potential predictive biomarker related to the mechanism of action of the experimental therapy. In this review article, we review recent innovative design extensions and adaptations to adaptive enrichment designs proposed during the last few years in the clinical trial methodology literature, both from Bayesian and frequentist perspectives.

Protocol-Stipulated Dose Modification to Manage Chemotherapy-Induced Peripheral Neuropathy in Children, Adolescents, and Young Adults With High-Risk Hodgkin Lymphoma.

PURPOSE: Brentuximab vedotin (BV) incorporation into frontline chemotherapy regimens improved outcomes for classic Hodgkin lymphoma (cHL). The shared mechanism of action of BV and vinca alkaloids as microtubulin inhibitors increased the potential risk of chemotherapy-induced peripheral neuropathy (CIPN). Rates of CIPN and use of protocol-stipulated dose modifications of a microtubulin inhibitor were examined on the Children's Oncology Group AHOD1331 study, which compared BV, doxorubicin, vincristine (VCR), etoposide, prednisone, cyclophosphamide (BV-AVE-PC; BV arm) with bleomycin containing doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC; standard arm) in patients with high-risk cHL ages 2-21 years. METHODS: AHOD1331 required clinician grading and reporting of ≥grade 2 CIPN. Protocol-stipulated dose modifications of VCR preceded modification of BV for ≥grade 2 CIPN in the BV arm, but only required modification of VCR for ≥grade 3 in the standard arm. Outcomes included CIPN rates, dose modification of microtubulin inhibitors by study arm, clinical factors associated with dose modifications, and event-free survival (EFS) by the presence of dose modification. RESULTS: Among the 582 patients who began protocol therapy, 112 developed ≥grade 2 CIPN. Cumulative incidence of CIPN did not differ by study arm (19.2 v 19.8%, P = .91). CIPN dose modifications occurred more frequently in the BV arm (9.5% v 2.8%, P = .001); however, most patients with CIPN on the BV arm received full-dose BV. EFS did not differ by the presence of dose modifications after accounting for study arm, age, sex, and stage, although older age was significantly associated with the risk of VCR dose modifications for CIPN. CONCLUSION: A staged dose modification plan for vinca alkaloids and BV as administered in AHOD1331 minimized the effect of incorporating a second microtubulin inhibitor on CIPN without compromising treatment efficacy in the BV arm.

Artificial intelligence-based digital pathology for the detection and quantification of soil-transmitted helminths eggs.

BACKGROUND: Conventional microscopy of Kato-Katz (KK1.0) thick smears, the primary method for diagnosing soil-transmitted helminth (STH) infections, has limited sensitivity and is error-prone. Artificial intelligence-based digital pathology (AI-DP) may overcome the constraints of traditional microscopy-based diagnostics. This study in Ucayali, a remote Amazonian region of Peru, compares the performance of AI-DP-based Kato-Katz (KK2.0) method to KK1.0 at diagnosing STH infections in school-aged children (SAC). METHODS: In this prospective, non-interventional study, 510 stool samples from SAC (aged 5-14 years) were analyzed using KK1.0, KK2.0, and tube spontaneous sedimentation technique (TSET). KK1.0 and KK2.0 slides were evaluated at 30-minute and 24-hour timepoints for detection of Ascaris lumbricoides, Trichuris trichiura, and hookworms (at 30-minute only). Diagnostic performance was assessed by measuring STH eggs per gram of stool (EPG), sensitivity of methods, and agreement between the methods. RESULTS: KK2.0 detected more A. lumbricoides positive samples than KK1.0, with detection rates for T. trichiura and hookworms being comparable. At 30-minutes, 37.6%, 23.0%, and 2.6% of the samples tested positive based on KK1.0 for A. lumbricoides, T. trichiura, and hookworms, while this was 49.8%, 24.4%, and 1.9% for KK2.0. At 24-hours, 37.1% and 27.1% of the samples tested positive based on KK1.0 for A. lumbricoides and T. trichiura, while this was 45.8% and 24.1% for KK2.0. Mean EPG between KK2.0 and KK1.0 were not statistically different across STH species and timepoints, except for T. trichiura at 24-hours (higher mean EPG for KK1.0, p = 0.036). When considering infection intensity levels, KK2.0 identified 10% more of the total population as low-infection intensity samples of A. lumbricoides than KK1.0 (p ≤ 0.001, both timepoints) and similar to KK1.0 for T. trichiura and hookworms. Varying agreement existed between KK1.0 and KK2.0 in detecting STH eggs (A. lumbricoides: moderate; T. trichiura: substantial; hookworms: slight). However, these findings should be interpreted carefully as there are certain limitations that may have impacted the results of this study. CONCLUSIONS: This study demonstrates the potential of the AI-DP-based method for STH diagnosis. While similar to KK1.0, the AI-DP-based method outperforms it in certain aspects. These findings underscore the potential of advancing the AI-DP KK2.0 prototype for dependable STH diagnosis and furthering the development of automated digital microscopes in accordance with WHO guidelines for STH diagnosis.

Attachment classification and early adversity predict perinatal partial hospital treatment response.

BACKGROUND: Depression and anxiety are common in the perinatal period. While most of those affected respond well to treatment, a subpopulation is more resistant. Understanding more about individuals who do not respond well to available treatments may improve care for this group. METHODS: We administered entry and exit self-report measures to 178 women who participated in a specialized partial hospitalization program for perinatal individuals. Baseline measures of anxiety, obsessive symptoms, sleep quality, early life adversity, and adult attachment security were examined as potential predictors of response to treatment. RESULTS: While no individual baseline survey predicted treatment response, clustering patients on the basis of a combination of self-report adult attachment styles and early life adversity yielded four distinct groups. A cluster with high attachment anxiety, high attachment avoidance, and childhood history of verbal and emotional abuse was less responsive to treatment than the other groups. CONCLUSIONS: Combining detailed information about self-report adult attachment style and early life adversity may improve prediction of treatment response in individuals with perinatal mood and anxiety disorders.