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AIMS: We aimed to investigate the association between being an immigrant and long-term prescription opioid use in Norway in 2010-2019. METHODS: Nested case-control study. The cases were all persons 18 years of age or older with long-term opioid use - that is, the use of prescription opioids longer than 3 months (N=215,642). Cases were matched to four controls who filled at least one opioid prescription, but never developed long-term opioid use in the study period (N=862,568) on sex, age and year of starting long-term/short-term opioid use. Being an immigrant was defined as being born outside of Norway to two foreign-born parents and four foreign-born grandparents. Adjusting for socioeconomic variables and clinical confounders, analyses were stratified on three age groups (18-44 years, 45-67 years and ⩾68 years). RESULTS: For the youngest age group, being an immigrant was inversely associated with long-term opioid use (adjusted odds ratio 0.75; 95% confidence interval [0.72-0.77]) compared with being native-born people. For this age group, the odds ratio differed between people born in Africa (0.56 [0.52-0.62]), Central or South America (0.70 [0.62-0.79]), Europe outside the European Union (EU) (0.71 [0.65-0.77]), Asia including Turkey (0.80 [0.77-0.84]) and EU/European Economic Area (EEA) (0.81 [0.77-0.85]). For the middle age group, increased odds were found for immigrants versus natives (1.05 [1.02-1.08]) in particular for those born in North America (1.26 [1.13-1.40]) and the EU/EEA (1.13 [1.09-1.18]). There was no association in the oldest group. CONCLUSIONS: Compared with native-born people, immigrants had lower odds of long-term opioid use among younger adults, higher odds among middle-aged and similar odds among older adults.

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Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.

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Introduction: The Cohen-Mansfield Agitation Inventory (CMAI) quantifies the frequency of agitation behaviors in elderly persons. This post hoc analysis of data from the brexpiprazole clinical program aimed to determine a meaningful within-patient change (MWPC) threshold for CMAI Total score among patients with agitation associated with dementia due to Alzheimer's disease. Methods: Data were included from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm trials of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease (ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584). Change in CMAI Total score (range 29-203; higher scores indicate higher frequency of agitation behaviors) from baseline to Week 12 was the primary endpoint in each trial. MWPC thresholds were estimated from anchor-based mean change analyses and receiver operating characteristic (ROC) curves. The Clinical Global Impression-Severity of illness (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales, both as related to agitation, were used as anchors. Empirical cumulative distribution functions (eCDFs) and probability density functions (PDFs) were plotted as supportive evidence. Distribution-based methods were also employed. Results: Data from 898 patients were analyzed (mean age, 73.7 years; mean baseline CMAI Total score, 73.8). The mean CMAI Total score change corresponding to a difference of small improvement vs. stable (CGI-S one-point decrease vs. no change), or minimally improved vs. no change (CGI-I rating of 3 vs. 4), ranged from -10.6 to -13.5 points. The mean CMAI Total score change corresponding to a difference of moderate improvement vs. stable (CGI-S two-point decrease vs. no change), or much improved vs. no change (CGI-I rating of 2 vs. 4), ranged from -20.2 to -25.7 points. ROC curve analyses generally produced smaller estimates of meaningful change. eCDFs and PDFs showed good distribution and separation of CMAI Total score change between CGI-S/CGI-I categories. In distribution-based analyses, the minimal detectable change for CMAI Total score (10.5-11.8 points) was generally lower than anchor-suggested thresholds. Conclusion: Triangulation of evidence from anchor- and distribution-based analyses supports an MWPC threshold for CMAI Total score of -20 points, with a threshold range of -15 to -25 points, in patients with agitation associated with dementia due to Alzheimer's disease.

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Amidst rising Parkinson's disease (PD) incidence in an aging global population, the need for non-invasive and reliable diagnostic methods is increasingly critical. This review evaluates the strategic role of transcranial sonography (TCS) in the early detection and monitoring of PD. TCS's ability to detect substantia nigra hyperechogenicity offers profound insights into its correlation with essential neuropathological alterations-namely, iron accumulation, neuromelanin depletion, and glial proliferation-fundamental to PD's pathophysiology. Our analysis highlights TCS's advantages, including its non-invasiveness, cost-effectiveness, and ease of use, positioning it as an invaluable tool for early diagnosis and continual disease progression monitoring. Moreover, TCS assists in identifying potential risk and protective factors, facilitating tailored therapeutic strategies to enhance clinical outcomes. This review advocates expanding TCS utilization and further research to maximize its diagnostic and prognostic potential in PD management, contributing to a more nuanced understanding of the disease.

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Advanced Glycation End-products (AGEs), with their prolonged half-life in the human body, are emerging as potent diagnostic indicators. Early intervention studies, focusing on AGE cross-link breakers, have shown encouraging results in heart failure patients, paving the way for disease progression monitoring and therapy effectiveness evaluation. AGEs are the byproducts of a non-enzymatic reaction where sugars interact with proteins, lipids, and nucleic acids. These compounds possess the power to alter numerous biological processes, ranging from disrupting molecular conformation and promoting cross-linking to modifying enzyme activity, reducing clearance, and impairing receptor recognition. The damage inflicted by AGEs through the stimulation of intracellular signaling pathways is associated with the onset of chronic diseases across various organ systems. This review consolidates the characteristics of AGEs and the challenges posed by their expression in diverse physiological and pathological states. Furthermore, it highlights the clinical relevance of AGEs and the latest research breakthroughs aimed at reducing AGE accumulation.

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Transient ischemic attack (TIA) is traditionally viewed as a self-resolving episode of neurological change without persistent impairments and without evidence of acute brain injury on neuroimaging. However, emerging evidence suggests that TIA may be associated with lingering cognitive dysfunction. Cognitive impairment is a prevalent and disabling sequela of ischemic stroke, but the clinical relevance of this phenomenon after TIA is less commonly recognized. We performed a literature search of observational studies of cognitive function after TIA. There is a consistent body of literature suggesting that rates of cognitive impairment following TIA are higher than healthy controls, but the studies included here are limited by heterogeneity in design and analysis methods. We go on to summarize recent literature on proposed pathophysiological mechanisms underlying the development of cognitive impairment following TIA and finally suggest future directions for further research in this field.

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Nontuberculous mycobacteria (NTM) are emerging as notable causative agents of opportunistic infections. To examine clinical significance, species distribution, and temporal trends of NTM in Denmark, we performed a nationwide register-based study of all unique persons with NTM isolated in the country during 1991-2022. We categorized patients as having definite disease, possible disease, or isolation by using a previously validated method. The incidence of pulmonary NTM increased throughout the study period, in contrast to earlier findings. Mycobacterium malmoense, M. kansasii, M. szulgai, and M. avium complex were the most clinically significant species based on microbiologic findings; M. avium dominated in incidence. This study shows the need for surveillance for an emerging infection that is not notifiable in most countries, provides evidence to support clinical decision-making, and highlights the importance of not considering NTM as a single entity.

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Aim: Medical literature revealed that there is a lack of information about the opinions of medical interns and residents about curricula provided to them during their undergraduate programs, either in a group of detached subjects or an incorporated and efficacious topic (ie, pathology). Purpose: To assess and compare the interns' and residents' perspectives towards Pathology as a subject. To recognize their opinions toward the relevance and application of Pathology while practicing clinically. Methods: This study was a cross-sectional online, self-administered questionnaire targeting interns and residents. The questionnaire consisted of 30 questions, enquiring about the demographic data, subject strength, teaching duration, interest in the subject, and usefulness of Pathology as a subject in clinical practice. Results: Overall, 103 participants completed the survey. The female and male percentage was 59.2% and 40.8% respectively. 86.4% of participants were interns, while 13.6% were residents. 87% of participants agreed that applying pathology during clinical practice is a skill that should be strengthened in the early stages of preclinical education of Medicine. A modest percentage believed that a practitioner could efficiently treat the majority of patients with no need to know the specifics of the pathological mechanisms involved. Most of the participants believed that pathology courses helped them in making a differential diagnosis, analysis of normal and pathological constituents, and dissection and identification of structures. Conclusion: This study highlights the positive perceptions of Jordanian interns and residents toward pathology courses. It also demonstrates that participants prefer an active and dynamic educational model with an emphasis on better integration of pathology courses and clinical experiences that fit their needs in clinical practice. Thus, we recommend future studies to compare the competencies of interns and residents enrolled in the courses with integrated medical curricula, of pathology versus those who studied the conventional medical curricula of pathology, as well as to evaluate their perceptions of medical education.

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Assessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer's disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach.

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Lung carcinoma, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), remains a significant global health challenge due to its high morbidity and mortality rates. The objsective of this review is to meticulously examine the current advancements and strategies in the delivery of CRISPR-Cas9 gene-editing technology for the treatment of lung carcinoma. This technology heralds a new era in molecular biology, offering unprecedented precision in genomic modifications. However, its therapeutic potential is contingent upon the development of effective delivery mechanisms that ensure the efficient and specific transport of gene-editing tools to tumor cells. We explore a variety of delivery approaches, such as viral vectors, lipid-based nanoparticles, and physical methods, highlighting their respective advantages, limitations, and recent breakthroughs. This review also delves into the translational and clinical significance of these strategies, discussing preclinical and clinical studies that investigate the feasibility, efficacy, and safety of CRISPR-Cas9 delivery for lung carcinoma. By scrutinizing the landscape of ongoing clinical trials and offering translational perspectives, we aim to elucidate the current state and future directions of this rapidly evolving field. The review is structured to first introduce the problem and significance of lung carcinoma, followed by an overview of CRISPR-Cas9 technology, a detailed examination of delivery strategies, and an analysis of clinical applications and regulatory considerations. Our discussion concludes with future perspectives and challenges, such as optimizing delivery strategies, enhancing specificity, mitigating immunogenicity concerns, and addressing regulatory issues. This comprehensive overview seeks to provide insights into the potential of CRISPR-Cas9 as a revolutionary approach for targeted therapies and personalized medicine in lung carcinoma, emphasizing the importance of delivery strategy development in realizing the full potential of this groundbreaking technology.

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The statistical significance of a clinical trial analysis result is determined by a mathematical calculation and probability based on null hypothesis significance testing. However, statistical significance does not always align with meaningful clinical effects; thus, assigning clinical relevance to statistical significance is unreasonable. A statistical result incorporating a clinically meaningful difference is a better approach to present statistical significance. Thus, the minimal clinically important difference (MCID), which requires integrating minimum clinically relevant changes from the early stages of research design, has been introduced. As a follow-up to the previous statistical round article on P values, confidence intervals, and effect sizes, in this article, we present hands-on examples of MCID and various effect sizes and discuss the terms statistical significance and clinical relevance, including cautions regarding their use.

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OBJECTIVE: To optimize the training strategy of large language models for medical applications, focusing on creating clinically relevant systems that efficiently integrate into healthcare settings, while ensuring high standards of accuracy and reliability. MATERIALS AND METHODS: We curated a comprehensive collection of high-quality, domain-specific data and used it to train several models, each with different subsets of this data. These models were rigorously evaluated against standard medical benchmarks, such as the USMLE, to measure their performance. Furthermore, for a thorough effectiveness assessment, they were compared with other state-of-the-art medical models of comparable size. RESULTS: The models trained with a mix of high-quality, domain-specific, and general data showed superior performance over those trained on larger, less clinically relevant datasets (P < .001). Our 7-billion-parameter model Med5 scores 60.5% on MedQA, outperforming the previous best of 49.3% from comparable models, and becomes the first of its size to achieve a passing score on the USMLE. Additionally, this model retained its proficiency in general domain tasks, comparable to state-of-the-art general domain models of similar size. DISCUSSION: Our findings underscore the importance of integrating high-quality, domain-specific data in training large language models for medical purposes. The balanced approach between specialized and general data significantly enhances the model's clinical relevance and performance. CONCLUSION: This study sets a new standard in medical language models, proving that a strategically trained, smaller model can outperform larger ones in clinical relevance and general proficiency, highlighting the importance of data quality and expert curation in generative artificial intelligence for healthcare applications.

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BACKGROUND: Research on temporomandibular disorder (TMD) responsiveness is scarce and limited regarding patients' representativeness. OBJECTIVE(S): This study aimed to estimate minimum clinically important difference (MCID) and substantial clinical benefit (SCB) among a large and diverse patient population regarding sex and age. METHODS: In this study, 162 patients participated from five hospitals. MCID and SCB in pain, functional disability and quality of life were examined with anchor-based methods. Patients' global impression of change was used as the anchor. Area under the curve (AUC) values were determined for testing accuracy. Changes from baseline and coefficient of variation by responsiveness status were calculated to explain the results of accuracy. RESULTS: SCB was estimated to be 2.18 for the numeric rating scale (NRS) for pain (AUC: 0.80 [95% CI: 0.72-0.88]) in all patients and 2.50 in women (AUC: 0.81 [95% CI: 0.71-0.89]). The estimated SCB of NRS for discomfort (1.50) and Jaw Functional Limitation Scale for mastication (1.35) had wide CIs for AUCs. Likewise, the estimated MCIDs of NRS for pain (0.80) and NRS for discomfort (1.50) had wide CIs for AUCs. Among non-responders who did not achieve the MCID of NRS for pain, the coefficient of variation was very high for all outcomes other than the NRS for pain. CONCLUSION: This study investigated the responsiveness of patients with TMD using a large and diverse patient sample. SCB in pain decrease can be used to assess the responsiveness of patients with TMD. Composite outcomes should be developed to estimate MCID.

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People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities. Several factors, including the HIV reservoir, coinfections, clonal hematopoiesis of indeterminate potential (CHIP), microbial translocation, and antiretroviral therapy, may contribute to the chronic state of inflammation. Within the innate immune system, macrophages harbor latent HIV and are among the prominent immune cells present in atheroma during the progression of atherosclerosis. They secrete inflammatory cytokines such as IL (interleukin)-6 and tumor necrosis-α that stimulate the expression of adhesion molecules on the endothelium. This leads to the recruitment of other immune cells, including cluster of differentiation (CD)8+ and CD4+ T cells, also present in early and late atheroma. As such, cells of the innate and adaptive immune systems contribute to both systemic inflammation and vascular inflammation. On a molecular level, HIV-1 primes the NLRP3 (NLR family pyrin domain containing 3) inflammasome, leading to an increased expression of IL-1ß, which is important for cardiovascular outcomes. Moreover, activation of TLRs (toll-like receptors) by HIV, gut microbes, and substance abuse further activates the NLRP3 inflammasome pathway. Finally, HIV proteins such as Nef (negative regulatory factor) can inhibit cholesterol efflux in monocytes and macrophages through direct action on the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1), which promotes the formation of foam cells and the progression of atherosclerotic plaque. Here, we summarize the stages of atherosclerosis in the context of HIV, highlighting the effects of HIV, coinfections, and antiretroviral therapy on cells of the innate and adaptive immune system and describe current and future interventions to reduce residual inflammation and improve cardiovascular outcomes among people living with HIV.

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BACKGROUND AND OBJECTIVE: Mediation analysis is used to gain insight into the mechanisms of exposure-outcome effects by dividing this effect into a direct and an indirect effect. One of the problems of mediation analysis is that in many situations, the standard error of the indirect effect is much lower than the standard errors of the total and direct effect. Because this problem is ignored in the epidemiological literature, the purpose of this paper was to illustrate this problem and to provide an advice regarding the statistical testing of indirect effects in mediation analysis. METHODS: To illustrate the problem of the estimation of the standard error of the indirect effect two real life datasets and several simulations are used. RESULTS: The paper shows that the problem of estimating the standard error of the indirect effect was most pronounced when the relationship between exposure and mediator and the relationship between mediator and outcome were equally strong. Furthermore, the magnitude of the estimation problem is different for different strengths of the mediation effect. CONCLUSION: The indirect effect in mediation analysis should not be tested for statistical significance but the importance of mediation should be evaluated by its clinical relevance.

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PURPOSE: Genetically predisposed breast cancer (BC) patients represent a minor but clinically meaningful subgroup of the disease, with 25% of all cases associated with actionable variants in BRCA1/2. Diagnostic implementation of next-generation sequencing (NGS) resulted in the rare identification of BC patients with double heterozygosity for deleterious variants in genes partaking in homologous recombination repair of DNA. As clinical heterogeneity poses challenges for genetic counseling, this study focused on the occurrence and clinical relevance of double heterozygous BC in South Africa. METHODS: DNA samples were diagnostically screened using the NGS-based Oncomine™ BRCA Expanded Research Assay. Data was generated on the Ion GeneStudio S5 system and analyzed using the Torrent Suite™ and reporter software. The clinical significance of the variants detected was determined using international variant classification guidelines and treatment implications. RESULTS: Six of 1600 BC patients (0.375%) tested were identified as being bi-allelic for two germline likely pathogenic or pathogenic variants. Most of the variants were present in BRCA1/2, including two founder-related small deletions in three cases, with family-specific variants detected in ATM, BARD1, FANCD2, NBN, and TP53. The scientific interpretation and clinical relevance were based on the clinical and tumor characteristics of each case. CONCLUSION: This study increased current knowledge of the risk implications associated with the co-occurrence of more than one pathogenic variant in the BC susceptibility genes, confirmed to be a rare condition in South Africa. Further molecular pathology-based studies are warranted to determine whether clinical decision-making is affected by the detection of a second pathogenic variant in BRCA1/2 and TP53 carriers.

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High-sensitivity C-reactive protein (hsCRP) has emerged as a critical biomarker in inflammation, offering insights into various chronic diseases. However, traditional blood-based assays for hsCRP measurement pose limitations regarding invasiveness and cost. In recent years, saliva has garnered attention as an alternative diagnostic medium, presenting a noninvasive and easily accessible option for biomarker analysis. Salivary hsCRP has thus emerged as a promising avenue for research and clinical application, offering potential advantages over blood-based assays. This comprehensive review aims to elucidate the biological basis of salivary hsCRP, its clinical applications, and methodologies for measurement. By exploring its diagnostic potential, prognostic value, and implications for treatment monitoring, this review highlights the potential impact of salivary hsCRP in modern medicine. Moreover, it emphasizes the need for continued exploration, validation, and integration of salivary hsCRP into routine clinical practice to realize its full potential for enhancing patient care and advancing personalized medicine approaches.

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Actinomyces organisms reside on mucosal surfaces of the oropharynx and the genitourinary tract. Polymicrobial infections with Actinomyces organisms are increasingly being reported in the literature. Since these infections differ from classical actinomycosis, lacking of specific clinical and imaging findings, slow-growing Actinomyces organisms can be regarded as contaminants or insignificant findings. In addition, only limited knowledge is available about novel Actinomyces species and their clinical relevance. The recent reclassifications have resulted in the transfer of several Actinomyces species to novel genera Bowdeniella, Gleimia, Pauljensenia, Schaalia, or Winkia. The spectrum of diseases associated with specific members of Actinomyces and these related genera varies. In human infections, the most common species are Actinomyces israelii, Schaalia meyeri, and Schaalia odontolytica, which are typical inhabitants of the mouth, and Gleimia europaea, Schaalia turicensis, and Winkia neuii. In this narrative review, the purpose was to gather information on the emerging role of specific organisms within the Actinomyces and related genera in polymicrobial infections. These include Actinomyces graevenitzii in pulmonary infections, S. meyeri in brain abscesses and infections in the lower respiratory tract, S. turicensis in skin-related infections, G. europaea in necrotizing fasciitis and skin abscesses, and W. neuii in infected tissues around prostheses and devices. Increased understanding of the role of Actinomyces and related species in polymicrobial infections could provide improved outcomes for patient care. Key messages Due to the reclassification of the genus, many former Actinomyces species belong to novel genera Bowdeniella, Gleimia, Pauljensenia, Schaalia, or Winkia.Some of the species play emerging roles in specific infection types in humans.Increasing awareness of their clinical relevance as an established or a putative pathogen in polymicrobial infections brings about improved outcomes for patient care.

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Objectives: This retrospective study aims to identify incidental findings in cone-beam computed tomography scans of patients irradiated for preoperative evaluation for implant placement and obtained using the same imaging unit as well as the same field of view. The incidence of each incidental finding, as well as the overall incidence, were calculated and the findings were ranked according to their clinical significance. Material and Methods: A total of 741 cone-beam computed tomography (CBCT) examinations with extended field of view (15 x 15 cm) were retrospectively evaluated for incidental findings (IFs). These were identified, recorded, classified as to their location, and ranked according to their clinical significance. Results: The vast majority of CBCT examinations presented at least one IF, resulting in a surprisingly high prevalence in total. If extreme anatomical variants are considered (nasal septum deviation, sinus septations etc.), the cumulative prevalence exceeds 99%. IFs of major significance, that may require immediate attention, are beyond 10% in frequency. Conclusions: We found high prevalence of incidental findings on cone-beam computed tomography examinations performed for preoperative evaluation for implant placement (99.5% if anatomical variants included). Most incidental findings were of minor significance. Although the number of incidental findings that require immediate attention is relatively low, there is a considerable number of cases that need periodic evaluation and/or referral.