Gene expression signature for predicting homologous recombination deficiency in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers and may also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a gene expression-based machine learning classifier for homologous recombination deficiency (HRD) in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.93 in MyBrCa validation datasets and 0.84 in TCGA TNBCs. Additionally, the classifier strongly segregated HRD-associated genomic features in TNBCs from TCGA, METABRIC, and ICGC. Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy.

Using B-mode ultrasound to evaluate Risser grading for the determination of skeletal maturity in adolescents.

INTRODUCTION: Rapid adolescent growth is associated with an increased risk of disease and disease progression. This study assesses the reliability and validity of non-ionising B-mode ultrasound for the assessment of skeletal maturity (Risser Grade) and offers procedural guidelines for its use. METHODS: Twenty-three female adolescents with primary-right-thoracic scoliosis (age: 13.8 (1.6) years) and twenty age-matched female control participants without scoliosis (age: 13.1 (1.8) years) were recruited. Skeletal maturity was determined from (i) a series of nine B-mode ultrasound images collected at sites equally spaced between the anterior and posterior superior iliac spines of the pelvis and (ii) clinical spine radiographs obtained as part of standard scoliosis care. Inter-rater reliability was assessed between a novice researcher and an experienced medical doctor. Concurrent-validity was assessed by comparing the location and degree of apophysis growth and fusion obtained via ultrasound with that obtained using radiograph Risser grading for scoliosis participants only. RESULTS: The inter-rater reliability of ultrasound Risser grading was strong [ICC(2,1): 0.99, p < 0.001]. High concurrent-validity was determined, with no difference in Risser grading identified between the radiograph and ultrasound grading methods (Wilcoxon signed-rank: Z = -1.93, p = 0.053). CONCLUSION: Ultrasound provides a reliable non-ionising alternative to the gold standard of Risser grading from radiographs to determine and monitor skeletal maturity. This study provides a detailed methodology for using ultrasound to assess skeletal maturity. IMPLICATIONS FOR PRACTICE: Rapid adolescent growth is associated with an increased risk of disease and disease progression. Therefore, accurately determining and monitoring skeletal maturity in these adolescents is crucial. This study assesses the reliability and validity of non-ionising B-mode ultrasound for the assessment of skeletal maturity and offers procedural guidelines for its use.

Determinants of the utilization of recognized traditional and complementary medicine service in Malaysia: a secondary analysis of a cross-sectional population-based survey.

INTRODUCTION: The utilization of traditional and complementary medicine (T&CM) services has witnessed a global increase over the past decades. Currently, seven practice areas are recognized in Malaysia: traditional Malay medicine, traditional Chinese medicine, traditional Indian medicine, homeopathy, Islamic medical practice, chiropractic, and osteopathy. Many global studies have investigated the general determinants of T&CM service utilization. However, there has been no comprehensive study reporting specific determinants of recognized T&CM service utilization. This study aimed to examine the prevalence and specific determinants of recognized T&CM service utilization in Malaysia at a national level. METHODS: This study is a secondary analysis of data from the National Health and Morbidity Survey (NHMS), a cross-sectional population-based survey conducted in Malaysia in 2015. A total of 6,207 respondents aged ≥18 years were included in this study. The associations of sociodemographic, health, and lifestyle factors with the utilization of the three T&CM service categories (traditional Malay medicine, traditional Chinese medicine, and other T&CM) were examined using three separate logistic regression analyses. RESULTS: The prevalence of recognized T&CM service utilization in the last 12 months was 19.3%, with 15.0% for traditional Malay medicine, 3.9% for traditional Chinese medicine, and 1.5% for other T&CM. The determinants of traditional Malay medicine service utilization were female sex; age range of 18-29 years; married or widowed/divorced status; Malay, Indigenous or other ethnicities; high household income; and being overweight/obese. The determinants of traditional Chinese medicine service utilization were the age range of 30-49 years, urban residential location, Chinese ethnicity, and adequate fruit and vegetable intake. No specific determinants were identified for other T&CM. CONCLUSION: This study provided novel evidence of a strong ethnocultural ownership towards traditional medicine. User profiles were distinctively different between varied T&CM services. Customized approaches to regulate, develop, and institutionalize specific T&CM services are crucial for fulfilling the unique needs of diverse communities.

Correction: Characterization of a Polyethylene Glycol-Amphotericin B Conjugate Loaded with Free AMB for Improved Antifungal Efficacy.

[This corrects the article DOI: 10.1371/journal.pone.0152112.].

The landscape of clinical trials research in inherited ophthalmic disease.

OBJECTIVE: To describe the current status of clinical trials of genetic eye diseases with identified molecular targets for future areas of research. METHOD: Data analysis of the clinical trials database on clinicaltrials.gov with keywords for eight common, genetically tractable inherited eye diseases and their common molecular targets was performed during the period from 20 March 2021 to 31 December 2023. RESULTS: Two hundred and eighty-eight trials involving our keywords have been identified, excluding 25 (8.7%) trials which were unknown (verification expired with no update), 14 (4.9%) trials which were terminated early and 6(2.1%) trials which were withdrawn. In total there were 243 (84.4%) trials included. Out of the 243 trials, 120 trials were completed, 76 trials were active and still open to recruitment and 44 trials were active without any more recruitment on the way. There were only 32 (13.2%) trials with posted results. CONCLUSIONS: A low percentage of results were posted for completed trials. However, current and future clinical trials in the genetic eye diseases with molecular targets identified, have a promising future. The results of these trials will enhance and allow a better understanding of the potential to develop treatments for these conditions.

A Cost Evaluation of COVID-19 Remote Home Monitoring Services in England.

BACKGROUND: Remote home monitoring services emerged as critical components of health care delivery from NHS England during the COVID-19 pandemic, aiming to provide timely interventions and reduce health care system burden. Two types of service were offered: referral by community health services to home-based care to ensure the right people were admitted to the hospital at the right time (called COVID Oximetry@home, CO@h); and referral by hospital to support patients' transition from hospital to home (called COVID-19 Virtual Ward, CVW). The information collected for the oxygen levels and other symptoms was provided via digital means (technology-enabled) or over the phone (analogue-only submission mode). This study aimed to evaluate the costs of implementing remote home monitoring for COVID-19 patients across 26 sites in England during wave 2 of the pandemic. Understanding the operational and financial implications of these services from the NHS perspective is essential for effective resource allocation and service planning. METHODS: We used a bottom-up costing approach at the intervention level to describe the costs of setting up and running the services. Twenty-six implementation sites reported the numbers of patients and staff involved in the service and other resources used. Descriptive statistics and multivariable regression analysis were used to assess cost variations and quantify the relationship between the number of users and costs while adjusting for other service characteristics. RESULTS: The mean cost per patient monitored was lower in the CO@h service compared with the CVW service (£527 vs £599). The mean cost per patient was lower for implementation sites using technology-enabled and analogue data submission modes compared with implementation sites using analogue-only modes for both CO@h (£515 vs £561) and CVW (£584 vs £612) services. The number of patients enrolled in the services and the service type significantly affected the mean cost per patient. CONCLUSIONS: Our analysis provides a framework for evaluating the costs of similar services in the future and shows that the implementation of these services benefit from the employment of tech-enabled data submission modes.

The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.

Filling the "GAP" in Real-World Assessment of Psoriatic Arthritis Disease Activity: Performance Characteristics of a Global/Pain Composite Endpoint.

INTRODUCTION: Some retrospective data sources, such as electronic health records in the USA, report composite outcome measures not fully validated in psoriatic arthritis (PsA). However, they often contain global assessments, such as a Physician Global Assessment (PhGA) and Patient Global Assessment (PatGA), along with patient-reported pain scores, which individually are considered validated in PsA. This research described the performance characteristics of a 3-item global assessment and pain (GAP) composite endpoint using data from the ixekizumab phase 3 PsA clinical trial program. METHODS: Discrimination of GAP was assessed by comparing placebo to active treatment arms. The magnitude of treatment effect and responsiveness were compared to Disease Activity Index for PsA (DAPSA), clinical DAPSA, DAPSA28, and Psoriatic Arthritis Disease Activity Score (PASDAS) using effect size (ES) and standardized response mean (SRM), respectively. Construct validity was evaluated through correlation among the composite endpoints, and with other physician- and patient-reported outcomes. Change in GAP was compared in patients who reached low disease activity (LDA) levels based on DAPSA, cDAPSA, and PASDAS vs those who did not. RESULTS: GAP discriminated between active treatment and placebo with statistically significant separation as early as week 1. The largest ES/SRM was seen with GAP (2.29/1.74) and PASDAS (2.47/1.68). GAP had the strongest correlation with PASDAS (0.81-0.92) and showed moderate correlations with patient-assessed physical function, low correlations with physician-assessed skin and nail psoriasis, and low to moderate correlation with physician-assessed enthesitis. A significantly greater improvement in GAP was seen in the groups achieving LDA states compared to those not (p < 0.001). CONCLUSION: The GAP composite, an abbreviated endpoint comprising measures common in electronic health records, has promising performance characteristics and could be used to address important clinical questions regarding outcomes and impact of PsA in existing datasets. CLINTRIALS. GOV IDENTIFIER: NCT01695239; NCT02349295.

When doctors are assessing patients with psoriatic arthritis in clinical trials, they use tools, which include questions that patients answer and questions that doctors answer, in addition to a physical exam, to help evaluate how patients are doing. In a routine clinical practice setting, all of these same tools may not be used because they take a longer time to document information during a patient office visit. The goals of this research were to (1) create a new tool, which uses questions that patients and doctors answer, to help doctors evaluate how patients with psoriatic arthritis are doing in routine clinical practice, and (2) to assess if this new tool works as well as older tools. The new tool has fewer questions for the doctor and patient to answer and may take less time to document information but may result in some symptoms that patients experience not being regularly assessed. Data from clinical trials were used to compare the new tool to older tools to evaluate if doctors are able to assess psoriatic arthritis the same way. The results of the study showed that doctors are able to assess patients with psoriatic arthritis similarly with the new tool compared to older tools. This information will increase awareness of the new tool and could make it easier for doctors to evaluate patients with psoriatic arthritis in routine clinical practice.

Neural mechanism underlying preview effects and masked priming effects in visual word processing.

Two classic experimental paradigms - masked repetition priming and the boundary paradigm - have played a pivotal role in understanding the process of visual word recognition. Traditionally, these paradigms have been employed by different communities of researchers, with their own long-standing research traditions. Nevertheless, a review of the literature suggests that the brain-electric correlates of word processing established with both paradigms may show interesting similarities, in particular with regard to the location, timing, and direction of N1 and N250 effects. However, as of yet, no direct comparison has been undertaken between the two paradigms. In the current study, we used combined eye-tracking/EEG to perform such a within-subject comparison using the same materials (single Chinese characters) as stimuli. To facilitate direct comparisons, we used a simplified version of the boundary paradigm - the single word boundary paradigm. Our results show the typical early repetition effects of N1 and N250 for both paradigms. However, repetition effects in N250 (i.e., a reduced negativity following identical-word primes/previews as compared to different-word primes/previews) were larger with the single word boundary paradigm than with masked priming. For N1 effects, repetition effects were similar across the two paradigms, showing a larger N1 after repetitions as compared to alternations. Therefore, the results indicate that at the neural level, a briefly presented and masked foveal prime produces qualitatively similar facilitatory effects on visual word recognition as a parafoveal preview before a single saccade, although such effects appear to be stronger in the latter case.

A single-day polychemotherapy regimen with proteasome inhibitor combinations for relapsed/refractory myeloma in the era of novel therapies.

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.

Needs of transgender children and adolescents presenting to an urban gender health program.

BACKGROUND: Youth who identify as transgender and gender diverse (TGD) are increasingly presenting to pediatric providers. Gender-affirming surgery is often delayed until after a patient reaches the age of majority; however, patients may desire surgery at a younger age. OBJECTIVE: We explore the specific clinical needs of this vulnerable population, including surgical requests. STUDY DESIGN: We present a cross-sectional study of patient intake interviews at time of presentation to our gender health program from 2017 to 2020. We summarize patient demographics, medical histories, and gender-affirming care needs by gender identity and age of presentation. RESULTS: Of 92 patients analyzed, those included were 19 trans girls, 55 trans boys, and 18 non-binary individuals. The median age of our sample was 15 (range 5-17). The median age (IQR) while first questioning gender was 10 (7-12). Sexual orientation was variable with 28 (43%) not sure/unknown. The majority of patients present for primary care services (grade schoolers 75%, early teens 78%, and late teens 77%, p = 0.97) and hormone management (grade schoolers 42%, early teens 62%, and late teens 77%, p = 0.06). Late teens were more likely to present for surgical services (49%) compared to grade schoolers (25%) and early teens (11%), p = 0.001. Prior psychiatric diagnoses were common in all age groups. Trans girls were interested in a variety of affirming procedures whereas trans boys and non-binary individuals primarily sought chest surgery (see summary figure). CONCLUSION: Pediatric gender affirming care needs are varied and multidisciplinary within our center. By age 16, about half of TGD individuals are seeking surgical services. On average, there was a 4-5 year delay from age at first questioning one's gender and presenting to our gender health program. Primary care physicians in particular may prepare to serve this complex population by familiarizing themselves with treatment needs, including developing a network of competent surgical referrals.

Breastfeeding Practices and Postpartum Weight Retention in an Asian Cohort.

This study examines relationships between breastfeeding practices and postpartum weight retention (PPWR) at 6 and 12 months postpartum among 379 first-time mothers participating in a clinical trial in Singapore. We categorized feeding modes at 6 months into exclusive breastfeeding, mixed feeding, and exclusive formula feeding. Participants were analyzed in two groups based on their PPWR assessment at 6 and 12 months postpartum, with complete datasets available for each assessment. We calculated PPWR by subtracting pre-pregnancy weight from self-reported weight at 6 and 12 months postpartum, defining substantial PPWR as ≥5 kg retention. Modified Poisson regression models adjusted for potential confounders were performed. At 6 and 12 months, 35% (n = 132/379) and 31% (n = 109/347) of women experienced substantial PPWR, respectively. Compared to exclusive breastfeeding, mixed feeding (risk ratio 1.85; 95% confidence interval 1.15, 2.99) and exclusive formula feeding (2.11; 1.32, 3.28) were associated with a higher risk of substantial PPWR at 6 months. These associations were slightly attenuated at 12 months and appeared stronger in women with pre-pregnancy overweight or obesity. This study suggests that breastfeeding by 6 months postpartum may help mitigate PPWR, particularly with exclusive breastfeeding. It also draws attention to targeted interventions to promote breastfeeding among women with overweight or obesity.

REST and RCOR genes display distinct expression profiles in neurons and astrocytes using 2D and 3D human pluripotent stem cell models.

Repressor element-1 silencing transcription factor (REST) is a transcriptional repressor involved in neurodevelopment and neuroprotection. REST forms a complex with the REST corepressors, CoREST1, CoREST2, or CoREST3 (encoded by RCOR1, RCOR2, and RCOR3, respectively). Emerging evidence suggests that the CoREST family can target unique genes independently of REST, in various neural and glial cell types during different developmental stages. However, there is limited knowledge regarding the expression and function of the CoREST family in human neurodevelopment. To address this gap, we employed 2D and 3D human pluripotent stem cell (hPSC) models to investigate REST and RCOR gene expression levels. Our study revealed a significant increase in RCOR3 expression in glutamatergic cortical and GABAergic ventral forebrain neurons, as well as mature functional NGN2-induced neurons. Additionally, a simplified astrocyte transdifferentiation protocol resulted in a significant decrease in RCOR2 expression following differentiation. REST expression was notably reduced in mature neurons and cerebral organoids. In summary, our findings provide the first insights into the cell-type-specific expression patterns of RCOR genes in human neuronal and glial differentiation. Specifically, RCOR3 expression increases in neurons, while RCOR2 levels decrease in astrocytes. The dynamic expression patterns of REST and RCOR genes during hPSC neuronal and glial differentiation underscore the potential distinct roles played by REST and CoREST proteins in regulating the development of these cell types in humans.

The complete mitochondrial genome data of Pholas orientalis (Gmelin, 1791) from Malaysia.

Pholas orientalis (angelwing clam) is a mollusc species found in the coastal areas of Southeast Asia. Despite its economic significance, genetic information on the species is lacking. In this study, a P. orientalis specimen was collected from Kedah, Malaysia, and its complete mitochondrial genome was assembled using whole-genome sequencing data generated on an DNBSEQ-G400 platform. The circular mitochondrial genome of P. orientalis is 18,995 bp in size and contains 12 protein-coding genes (PCGs), 22 tRNAs, two rRNAs, and three control regions (D-loops). All genes are located on the heavy strand. The mitogenome has a base composition of 25.4 % A, 41.5 % T, 22.1% G, and 11 % C, exhibiting a bias towards AT content (66.9 %). The mitochondrial genomes of P. orientalis and 11 other Pholadoidea species were included in a phylogenetic analysis, which indicated that P. orientalis is closely related to Xyloredo nooi. The data reported in this study represents the first time that a Pholas mitochondrial genome has been reported. Such data will contribute to the better understanding of genetic relationships between P. orientalis and its relatives, leading to informed conservation and sustainable utilization of the species.

Antibody glycan quality predicted from CHO cell culture media markers and machine learning.

N-glycosylation can have a profound effect on the quality of mAb therapeutics. In biomanufacturing, one of the ways to influence N-glycosylation patterns is by altering the media used to grow mAb cell expression systems. Here, we explore the potential of machine learning (ML) to forecast the abundances of N-glycan types based on variables related to the growth media. The ML models exploit a dataset consisting of detailed glycomic characterisation of Anti-HER fed-batch bioreactor cell cultures measured daily under 12 different culture conditions, such as changes in levels of dissolved oxygen, pH, temperature, and the use of two different commercially available media. By performing spent media quantitation and subsequent calculation of pseudo cell consumption rates (termed media markers) as inputs to the ML model, we were able to demonstrate a small subset of media markers (18 selected out of 167 mass spectrometry peaks) in a Chinese Hamster Ovary (CHO) cell cultures are important to model N-glycan relative abundances (Regression - correlations between 0.80-0.92; Classification - AUC between 75.0-97.2). The performances suggest the ML models can infer N-glycan critical quality attributes from extracellular media as a proxy. Given its accuracy, we envisage its potential applications in biomaufactucuring, especially in areas of process development, downstream and upstream bioprocessing.