Communications medicine最新文献

Background: The pathological state of human epidermal growth factor receptor-2 (HER2) determines the treatment strategies. Immunohistochemistry (IHC) and in situ hybridization (ISH) are the only two recognized diagnostic methods for HER2-positive (HER2 + ). IHC, although widely used, has limited reliability and often requires further confirmation by ISH for IHC ≤ 2 + . Furthermore, studies have demonstrated that HER2-low patients may still benefit from HER2-targeted therapy, highlighting the need for accurate and sensitive detection methods.

Methods: In this study, we designed the molecular beacon (MB) for HER2 amplification detection. Subsequently, the in-situ dual-lighting system (ISDLS) was established by combining MB-based loop-mediated isothermal amplification (LAMP) and tyramide signal amplification (TSA)-based IHC for HER2 in-situ nucleic acid and protein detection in a single sample, and was verified in both cell line slides and human tumor sections. To better elucidate the significance of our study, we compared the test results with clinical reports.

Results: Here, we show that, in a single sample, satisfactory nucleic acid and protein signals are obtained, especially in human tumor sections within one day. The detection rate for clinical IHC ≥ 1+ and fluorescence in situ hybridization amplification (FISH + ) sections reaches 100%, and the detection rate of clinical FISH- sections reaches 77.8%.

Conclusions: ISDLS enables the spatial in-situ distribution of amplified nucleic acid and protein signals in one section, providing a basis for multidimensional analysis of diseases. ISDLS is also expected to improve the speed, sensitivity, and accuracy of detection compared to other methods.

Background: Loudness hyperacusis may alter brain function beyond the discomfort elicited by regular sound levels. Yet, the neuroscientific literature of hyperacusis has largely focused on the sensory neural components, and often in the context of other comorbid conditions. Our goal was to investigate brain-wide neural interactions associated with loudness hyperacusis using resting-state fMRI and machine learning classification.

Methods: Fourteen young, healthy adults experiencing hyperacusis were recruited and compared to twenty-five age-, gender-, and education-matched control individuals. All participants had normal hearing thresholds and they were classified as having hyperacusis based on having a score greater than 22 on the Hyperacusis Questionnaire (HQ). Functional connectivity measures were used in a machine learning model that distinguished participants with hyperacusis from controls. Model weights were further analyzed systematically to reveal the cognitive brain networks and regional hubs where functional coupling was significantly altered in hyperacusis.

Results: Here, we observe that participants with hyperacusis are distinguishable from control individuals using a functional connectivity-based classification model, which yields a classification F1-score of 0.679. Owing to optimized feature selection, the model coefficients capture highly specific neural connectivity differences between the groups, including brain regions and networks implicated in semantic processing, working memory, emotion processing, and self-regulation. Furthermore, network connectivity measures, scaled by model-informed coefficients, explain up to 53% of the variance in individual HQ scores.

Conclusions: Through rigorous data-driven modeling, we characterize the reduced sound tolerance condition of loudness hyperacusis as being associated with atypical spontaneous connectivity across cognitive networks that extend beyond the auditory system. Such improved knowledge of the condition validates patient experiences and has implications for future treatments and assessments.

Background: Clear communication is essential for the effective uptake of public health interventions promoting protective behaviours for respiratory infection control. The emergence of novel infectious diseases, particularly the COVID-19 pandemic, has highlighted the need for rapid adaptation of established and new behavioural practices. However, there remains limited knowledge concerning effective strategies for disseminating risk-reduction information and predicting population responses.

Methods: This systematic review and meta-analysis (PROSPERO: CRD42020198874) assessed the effectiveness of these interventions using behavioural science frameworks, including MINDSPACE contextual influencers and behaviour change techniques (BCTs), to identify key components and mechanisms of action (MoAs). Twenty-four full-text articles, comprising 36 randomised controlled trials (RCTs) across 11 countries, were included via electronic databases (MEDLINE, EMBASE, PsycINFO, Scopus) and other sources (grey literature, Google Scholar, and reference lists) searched to March 2022.

Results: Here, we show that interventions mainly target social distancing, mask wearing, hand washing, and various behavioural intentions and actual behaviours, using a median of three-arm study designs with passive comparators. Interventions include a median of two contextual influencers and four BCTs. Behaviour intention is the most frequently applied mechanism of action. Study quality is moderate. Narrative synthesis of 16 full-texts (26 RCTs) shows significant effects, while network meta-analysis of 16 full-texts (21 RCTs) indicates that prosocial messages, particularly those referencing loved ones, are effective in reducing the risk of respiratory infections (d = 0.09; 95% CrI=0.06-0.14; CINeMA: Low).

Conclusions: Although further research is needed, the review provides insight into designing public health messages that effectively improve protective behaviours for respiratory infection control.

Background: Early detection of drug-induced liver injury (DILI) during drug development is crucial for reducing drug attrition and ensuring the safety of patients. A versatile, biologically interpretable, and dose-dependent screening approach is therefore needed to inform early stop/go decisions and therapeutic margins.

Methods: We have developed AEGIS (Apoptotic Effector Genes In Safety), a preclinical DILI risk screening and prioritization tool that quantifies dose dependent perturbation of apoptosis-regulating transcription factors from transcriptomics data. We profiled transcriptomic responses after short exposures across primary human hepatocytes (PHH), HepG2/C3A cells, RAW 264.7 cells, and an acute Balb/c mouse study. From these profiles, AEGIS provides quantitative risk scores to rank and prioritize compounds and exposures.

Results: Here we show that AEGIS distinguishes compounds with different degree of DILI concern, achieving 86% specificity, 75% sensitivity and 90% precision in PHHs. We demonstrate versatility in data type usage and clinical translation of AEGIS with accurate predictions across species, in vitro and in vivo models, and therapeutic modalities. In addition, we apply AEGIS in a precision medicine context during drug-development within the pharmaceutical industry and investigate the contribution of underlying liver disease on DILI severity. Our findings indicate that cells from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) develop more severe DILI from treatment with troglitazone, aligning with preclinical observations.

Conclusions: Using AEGIS early in drug discovery exemplifies a more efficient approach to identify and mitigate potential safety concerns. This can reduce the need for animal testing, and accelerates drug discovery, ultimately providing the right medicines to patients more quickly.

Background: Cholestatic liver disease disproportionately affects South Asians, yet they remain underrepresented in genomic studies. This recall study aimed to recall volunteers from a British South Asian genetic cohort that were considered to be at high risk of cholestatic liver disease based on their genotype or phenotype.

Methods: Cases were defined as participants with rare (minor allele frequency <1%) heterozygous loss of function (LoF) variants in ABCB4 and ABCB11 (genotype re-call) or with a previous intrahepatic cholestasis of pregnancy (ICP) diagnosis (ICD10 O26.6). Cases were matched 1:1 to controls. A detailed medical and family history was taken along with fasting anthropometric and transient elastography (TE) measurements and blood samples.

Results: Out of 22 eligible volunteers, 9 (41%) participate in the recall (8/9 genotype and 1/9 phenotype recall). Among the recalled cases there are 5 ABCB4 LoF, 3 ABCB11 LoF, and 1 ICP phenotype. Of these, 5/9 (55.6%) exhibit findings suggestive of liver involvement (genotype re-call). Specifically, 2/5 (50%) have increased liver stiffness on TE with one also demonstrating abnormal liver blood tests. 2/5(40%) report at least 2 cholestatic symptoms and an additional 1/5 (20%) demonstrates abnormal liver blood tests without increased liver stiffness.

Conclusions: This study shows findings suggestive of liver involvement in 55.6% of volunteers, underscoring the potential of rare heterozygous ABCB4/11 variants as markers for identifying individuals at high risk of developing cholestatic liver disease. Consequently, individuals at higher genetic risk benefit from monitoring, personalised treatment and prevention strategies for cholestatic liver disease.

Background: Electronic health records are increasingly used to conduct pregnancy-related research as pregnant women are under-represented in research. Creating a register of pregnancies by combining data from primary and secondary care will further facilitate research in pregnancy. This work describes the construction of an algorithm to create a unified pregnancy cohort in the QResearch database during the emergency phase of the COVID-19 pandemic.

Methods: National primary care records in the QResearch® database were linked to patient-level data from Hospital Episode Statistics (HES) datasets. Females aged 15-50 years with a pregnancy outcome recorded between 30 December 2020 and 30 September 2022 were included. Pregnancy (delivery/loss) episodes were identified and cohort demographics reported using a three-stage algorithm. Pregnancy start dates were derived using a combination of HES and primary care data, or individually estimated where no corresponding date could be identified.

Results: 266,758 women with 279,027 pregnancies are captured in the register. 232,673 pregnancies (83.4%) are deliveries (99.5% livebirths and 0.5% stillbirths) and 46,354 (16.6%) pregnancies are pregnancy losses. Pregnancy losses are highest amongst those of Caribbean (23.1%; n = 781) ethnicity and lowest in those of Pakistani ethnicity (13.9%, n = 1,579). 82.4% of pregnancies are derived from HES maternity records, 10.6% from primary care records, 3.4% from HES Admissions, and 3.6% from HES Procedures.

Conclusion: The construction of a pregnancy register in QResearch® offers a valuable resource for future research. Its methodology can be adapted to construct new cohorts over any period, providing a comprehensive resource on pregnancy outcomes and events.

Background: Androgen receptor pathway inhibitors (ARPI) are commonly used in addition to androgen deprivation therapy (ADT) for metastatic prostate cancer (mPC). Despite preliminary results suggesting effects of ADT+ARPI on cognition, there is limited data on their impact in older adults. The objective was to assess cognition in mPC patients ≥70 years receiving ADT+ARPI.

Methods: This observational study (COG-PRO trial, NCT02907372, registered on 26/07/2016) recruited castration-resistant mPC patients (aged ≥70) receiving ADT+ARPI, patients receiving ADT alone, and healthy controls (HC). Cognition was prospectively assessed using a self-report questionnaire (subjective cognition) and cognitive tests addressing six domains: processing speed/attention, working memory, verbal memory, visual memory, visuospatial abilities, and executive functions (objective cognition). Rates of patients with impairment before ARPI initiation and decline after 3, 6 and 12 months were estimated using international recommendations. Adjusted scores were then analyzed with linear models.

Results: We report that at baseline (before starting ARPI for ADT+ARPI patients), objective cognitive impairment affects 36 (51%), 5 (26%) and 3 (10%) ADT+ARPI patients, ADT patients and HC, respectively. After 3 and 6 months of follow-up, adjusted scores show poorer subjective cognition in ADT+ARPI patients than in ADT patients (p ≤ 0.033). ADT+ARPI patients also have lower objective performance in processing speed/attention domain at all visits (p ≤ 0.010).

Conclusions: Although limited by small sample sizes, our study shows that ARPI + ADT can increase the risk of impacting objective and subjective cognition in older adults with mPC, compared to ADT alone. Clinician should use specific measures of objective and subjective cognition to assess ARPI-induced cognitive changes.

Background: Healthcare professionals experience high levels of burnout and chronic stress, which further jeopardizes their optimism and mental resilience.

Methods: The study involved 175 health professionals (46 doctors, 56 nurses, 27 nursing assistants, 23 ward assistants, 23 paramedical workers) of the Sismanogleio General Hospital of Athens, aged 26-65. Participants were administered an electronic questionnaire, which included socio-demographic data and work-related information, the Revised Life Orientation Test (LOT-R) and the Connor-Davidson Resilience Scale (CD-RISK-25). The data analysis was conducted using SPSS, with Descriptive and Inferential Statistics methods.

Results: The results reveal moderate levels of mental resilience (Mean=65.23, Std. Dev.=15.44) and moderate levels of optimism (Mean=12.75, Std. Dev.=2.89) among participants. Health professionals' levels of optimism are positively correlated with their levels of mental resilience (rho = 0.208, p = 0.006). The levels of optimism and mental resilience do not differ according to gender, marital status, or years of work experience (p = 0.612, p = 0.458, p = 0.214, respectively), but differ according to age (p < 0.001). Health professionals aged 60+ show the highest levels of mental resilience, while paramedical workers demonstrate greater optimism compared to physicians.

Conclusions: The development of targeted training and support programs aimed at strengthening optimism and mental resilience among healthcare professionals may be beneficial.

Background: Chronic kidney disease is a growing global health concern, requiring kidney replacement therapy for survival. In Brunei, kidney failure incidence and prevalence are among the highest globally. Despite a peritoneal dialysis preference policy, uptake remains low, straining financial and human resources. With dialysis costs and demand for skilled healthcare workers projected to rise significantly, this study evaluates the cost effectiveness, budget impact, and human resource requirements of alternative dialysis policies to inform sustainable policy decisions.

Methods: A Markov model was developed to compare the costs and health outcomes of three policy options under the government and societal perspective: (i) Current Practice, (ii) Automated Peritoneal Dialysis (APD)-first policy, and (iii) Continuous Ambulatory Peritoneal Dialysis (CAPD)-first policy, in which new patients start dialysis with either APD or CAPD respectively unless contraindicated. Budgetary and human resource impacts of each policy were estimated over a five-year period.

Results: Although both CAPD-first and APD-first policies show improved health and cost savings relative to the current policy, the APD-first policy is dominant (most cost effective) from the societal and government perspectives. Under the current policy, meeting the demand for Hemodialysis (HD) will require an additional 7 nephrologists and 230 HD nurses, whereas the APD and CAPD-first policies will significantly reduce workforce needs over the next 5-year period.

Conclusions: Findings suggest that Brunei's current policy is not the most cost-effective or sustainable option. A peritoneal dialysis-first approach could generate significant cost savings and reduce additional demand for scarce nephrologists and dialysis nurses. Our results highlight the need to integrate workforce planning into economic evaluation to inform sustainable dialysis policies.

Background: Biological age derived from DNA methylation (mAge) reflects aging-related physiological changes and the risk of age-related diseases. However, the association between oral microbiome and mAge remains unclear.

Methods: We examined associations between mAge, physical and cognitive function, and the oral microbiome in 311 community-dwelling, predominantly Chinese adults aged 85 years or older. Oral microbial composition was assessed using 16S rRNA sequencing, and mAge was estimated using four established epigenetic clocks: HorvathAge, HannumAge, PhenoAge, and GrimAge.

Results: In this cohort (median chronological age = 88.6 years; median DNA methylation-based biological age = 81.4 years), individuals with lower mAge deviation, corresponding to a younger biological age, exhibit lower oral microbial alpha diversity based on Simpson's index. While no taxa differences reach significance after correction for multiple testing, several short-chain fatty acid-producing genera, such as Prevotella_7 and Veillonella, show nominal associations with both mAge deviation and methylation at aging-related CpG sites, particularly in neurologically relevant genes. Higher abundance of Prevotella_7 species is associated with better cognitive performance (Mini-Mental State Examination), whereas Alloprevotella is linked to poorer cognition.

Conclusion: Our findings highlight that, as far as we aware, previously unrecognized oral microbiome composition links to lower mAge deviation and better cognitive function among the oldest-old, suggesting a potential role of the oral microbiome in promoting healthy aging and informing future mechanistic investigations.