Abstract

Background. Rasagiline or pramipexole monotherapy has been suggested for the management of early Parkinson’s disease (PD). The aim of this research was to systematically review the clinical efficacy and safety of rasagiline or pramipexole in early PD (defined as disease duration ≤5 years and Hoehn and Yahr stage of ≤3). Methods. Randomized controlled trials (RCTs) of rasagiline or pramipexole for early PD published up to September 2021 were retrieved. Outcomes of interest included changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II and III and the incidence of adverse events. Standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were calculated, and heterogeneity was measured with the I2 test. Results. Nine rasagiline and eleven pramipexole RCTs were included. One post hoc analysis of one rasagiline study was included. Five studies for each drug were included in meta-analyses of the UPDRS scores. The rasagiline meta-analysis focused on patients receiving 1 mg/day. Rasagiline and pramipexole significantly improved UPDRS Part II and III scores when compared to placebo. Significant heterogeneity among the studies was present (I2 > 70%). Neither rasagiline nor pramipexole increased the relative risk for any adverse events, serious adverse events, or adverse events leading to withdrawal when compared with placebo. Conclusion. Applying a Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to summarize the evidence, we found moderate confidence in the body of evidence for the efficacy of rasagiline or pramipexole in early PD, suggesting further well-designed, multicenter comparative RCTs remain needed.

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized clinically by bradykinesia, tremor, rigidity, and postural instability and histologically by neuronal inclusions composed of α-synuclein. Nonmotor symptoms including olfactory dysfunction, rapid eye movement, sleep behavior disorder, mood disorders, and autonomic dysfunction often precede the appearance of motor symptoms by several months or years [1, 2]. These motor and nonmotor symptoms can adversely affect a patient’s quality of life [3]. The incidence of PD is rising and increases with age [4, 5].

Early management of PD could prolong the ability of a patient to stay in working life and improve their overall quality of life [6, 7]. Levodopa is widely considered one of the most effective treatments for PD, but its use is often delayed because of drug-induced dyskinesias and wearing-off and on-off fluctuations [8, 9]. Alternatives to levodopa in early pharmacologic treatment of PD are dopamine agonists and monoamine oxidase B (MAO-B) inhibitors [10, 11]. A meta-analysis by Chang and coworkers (2017) [12] showed the irreversible inhibitor of MAO-B inhibitor rasagiline to have benefits both as a monotherapy and in combination with another intervention. The safety profile of rasagiline was similar to that of placebo in a systematic review of its use in PD patients [13]. Pramipexole, a nonergoline, D3-preferring dopamine agonist, is another treatment option for the management of motor symptoms associated with PD [14]. A recent systematic review showed that combined pramipexole and levodopa therapy was superior to levodopa monotherapy for the improvement of clinical symptoms in PD patients [15].

Prior systematic reviews evaluating the efficacy and safety of either rasagiline or pramipexole have evaluated patient populations at all stages of the disease. The goal of this study was to focus on the safety and efficacy of these drugs in early PD. Defining early PD in our review was based on the duration of PD in affected patients (five years or less) as well as the presence of mild to moderate symptoms based on the Hoehn and Yahr scale. The Hoehn and Yahr scale is commonly used in clinical studies to stage the level of functional disability and impairment seen in PD patients [16].

Results
4.1. Description of the Included Rasagiline Studies
The key characteristics of the nine rasagiline studies are reported in Table 1. One study [21] compared pramipexole and rasagiline as interventions and is included in this portion of the analysis. One post hoc analysis of a randomized controlled trial [22] met the inclusion criteria and was included in the systematic review. There were a total of 2121 patients in the studies, and 1059 patients were on rasagiline: 738 patients had a dose of 1 mg/day, 307 had a dose of 2 mg/day, and 14 had a dose of 4 mg/day. The mean age of study populations ranged from 59.3 to 70.2 years. The mean duration of PD ranged from 2.5 months to 4.8 years. The proportion of the study population who were males in the intervention groups ranged from 42.9 to 76.9%. There were four studies where other PD medications were either discontinued before the study or patients were PD-drug naïve [21, 23–25]. The rest of the studies allowed other PD medications with stable dosage for more than 4 weeks before the start of the study [26–29]. Rescue LD was accepted in one rasagiline study if PD symptoms worsened, and the current therapy did not relieve the symptoms [28]. Hoehn and Yahr stage was ≤3 in every study. The overall discontinuation rates were 7.3% and 10.7% in the rasagiline and placebo groups, respectively. One study reported seven discontinued patients without indicating which intervention the patients were using [27].

Abstract

Osteoporosis (OP) is a metabolic bone disease with a high incidence rate worldwide. Its main features are decreased bone mass, increased bone fragility and deterioration of bone microstructure. It is caused by an imbalance between bone formation and bone resorption. Ginsenoside is a safe and effective traditional Chinese medicine (TCM) usually extracted from ginseng plants, having various therapeutic effects, of which the effect against osteoporosis has been extensively studied. We searched a total of 44 relevant articles with using keywords including osteoporosis, ginsenosides, bone mesenchymal cells, osteoblasts, osteoclasts and bone remodeling, all of which investigated the cellular mechanisms of different types of ginsenosides affecting the activity of bone remodeling by mesenchymal stem cells, osteoblasts and osteoclasts to counteract osteoporosis. This review describes the different types of ginsenosides used to treat osteoporosis from different perspectives, providing a solid theoretical basis for future clinical applications.

Introduction

Osteoporosis (OP) is a metabolic bone disease characterized by decreased bone mass and destruction of bone tissue microstructure, leading to increased bone fragility and susceptibility to fractures ( Gopinath, 2023 ). A global epidemiological survey on osteoporotic vertebral fractures showed that one in three women and one in five men over the age of 50 will be directly affected by osteoporosis for the rest of their lives ( Laird et al., 2023 ). A study on the prediction of hip fractures in Asia estimated that by 2050, the direct cost of osteoporotic fractures in Asia alone may reach at least $15 billion per year ( Cheung et al., 2018 ). Therefore, early detection and treatment of osteoporosis is crucial for preventing fractures and reducing the burden on the global health care system.

Normal bone homeostasis in the human body is mainly maintained by osteoblasts differentiated from bone marrow mesenchymal stem cells (BMSCs) and osteoclasts produced by the fusion of monocytes and macrophages ( Guo et al., 2023 ; Kular et al., 2012 ), which participate in bone reconstruction and exert the sequential function of absorbing old bone and forming new bone ( Harris et al., 2023 ; Iantomasi et al., 2023 ) ( Fig. 1 ). The main cause of OP is aging, while secondary causes include genetic diseases, endocrine diseases, gastrointestinal diseases, blood diseases, neurological diseases, rheumatism and autoimmune diseases ( Patel and Wairkar, 2023 ). In addition, lifestyle changes, such as vitamin D and calcium deficiency, high salt intake, alcohol consumption, and smoking, also significantly increase the risk of osteoporosis. These factors can lead to an imbalance in bone cell activity and disrupt the dynamic cycle of bone formation and absorption, thereby affecting bone homeostasis and exacerbating OP ( Beekman et al., 2023 ).

Conclusion

In recent years, there has been increasing research on the treatment of osteoporosis with ginsenosides. Therefore, this review describes the possible mechanisms of different types of treatment for osteoporosis from three aspects, BMSCs, osteoblasts, and osteoclasts, and summarizes their specific signaling pathways or key factor mechanisms. However, this treatment method is still in the initial stage of clinical transformation, and there are still many obstacles between its experimental results and clinical application, such as in terms of combination therapy, drug delivery pathways, bioavailability, and combination with biochemical materials. With increasing attention given to the role of ginsenosides in bone reconstruction, ginsenosides may become a new drug for treating osteoporosis and promoting fracture healing and a powerful candidate for cytokines in tissue engineering bone.

Abstract

• Delayed-onset seizures after deep brain stimulation (DBS) surgery were seldom reported in previous studies. We studied 341 PD patients who underwent STN-DBS surgery from 2006 to 2021 in our department retrospectively.

• Five patients experienced seizures after DBS surgery with an incidence of 1.47 %. All 5 seizures cases were characterized as delayed-onset with an average time of 12 days postoperatively, which was different from the previous studies. In the further risk factors analysis of seizures, we found that the average diameter of peri-electrode edema of patients with seizures was larger than the average diameter of patients without seizures, which indicated that peri-electrode edema was risk factor for delayed-onset seizures after DBS surgery.

• Further multivariate analysis confirmed the result. Our study is the first report focusing on clinical characteristics and risk factors of delayed-onset seizures after DBS surgery based on a case series.

• Although DBS related seizure is uncommon complication, patients who experienced seizures are still exposed in risks of trauma and damage to the implanted simulator. We believe that these findings were useful for prevention and management of seizures associated with DBS surgery.

Introduction

Deep brain stimulation (DBS) is a well-established surgical therapy for some movement and psychiatric disorders. Patients are exposed in risks of trauma and implanted simulator damage when seizures occur, though seizures are not common postoperative adverse event of deep brain stimulation surgery. Previous studies indicated that the risk factors for seizures related to DBS included hemorrhage, peri-electrode edema, and increased age [1, 2, 3]. Most of the seizures occurred during electrode implantation procedures or within 48 h after DBS surgery [1, 2, 3], and delayed-onset seizures were seldom reported. However, this seizures incidence time-point presents quite different from those reports when retrospectively screening those PD patients who underwent subthalamic nucleus (STN) DBS in our center. We found that the seizures after DBS surgery were mainly delayed-onset (1–2 weeks after surgery). Therefore, this study summarized the clinical characteristics of delayed-onset seizures after DBS surgery and analyzed related risk factors.

Conclusions

Delayed-onset seizure after STN-DBS treating PD patients was uncommon with an incidence of 1.47 %. The seizures were transient and self-limiting, not easily developing into chronic epilepsy. Peri-electrode edema was a risk factor for delayed-onset seizures after DBS surgery. Patients with an average peri-electrode edema diameter > 2.70 cm had a higher risk to develop seizures.

Abstract

Nowadays, it is an established concept that the capability to reach a specialised cell identity via differentiation, as in the case of multi- and pluripotent stem cells, is not only determined by biochemical factors, but that also physical aspects of the microenvironment play a key role; interpreted by the cell through a force-based signalling pathway called mechanotransduction. However, the intricate ties between the elements involved in mechanotransduction, such as the extracellular matrix, the glycocalyx, the cell membrane, Integrin adhesion complexes, Cadherin-mediated cell/cell adhesion, the cytoskeleton, and the nucleus, are still far from being understood in detail. Here we report what is currently known about these elements in general and their specific interplay in the context of multi- and pluripotent stem cells. We furthermore merge this overview to a more comprehensive picture, that aims to cover the whole mechanotransductive pathway from the cell/microenvironment interface to the regulation of the chromatin structure in the nucleus. Ultimately, with this review we outline the current picture of the interplay between mechanotransductive cues and epigenetic regulation and how these processes might contribute to stem cell dynamics and fate.

Introduction

One of the basic principles enabling multicellular life is the differentiation of stem cells (SCs), into specialised cells with a defined identity, shape, and function ( McBeath et al., 2004 ) ( Tewary et al., 2018 ). SCs are defined as cells that are clonogenic, which defines their capability of both, self-renewing and retaining multilineage differentiation potency. In vertebrates, the Zygote represents the earliest stem cell (totipotent) in ontogeny, from which originate the pluripotent stem cells (PSCs) of the inner cell mass of the blastocyst ( Dean et al., 2003 , Smith, 2017 ). Soon thereafter, PSCs continue to expand during embryo development becoming progressively committed in their cell fate and acquiring a more restricted potency ( Dean et al., 2003 , Osorno et al., 2012 , Smith, 2017 ). Even at the end of embryogenesis, when the organism is fully formed, and its organs are composed of functionally mature cells, some SCs are still present. These cells, which possess a more limited differentiating potential (multipotent), in turn, give rise to a progeny of precursor cells and, finally, to functionally mature cells. Some examples are represented by the hematopoietic SCs in the bone marrow, the intestinal SCs in the gut’s crypts, the epithelial SCs in the epidermis or the mesenchymal stem cells (MSCs) which play an important role in the maintenance and regeneration of bones and cartilage ( Barker, 2014 , Evans et al., 2013 , Guan et al., 2012 , Tewary et al., 2018 , Watt, 2002 , Weissman, 2000 ).

The inherent high level of plasticity characterising SCs is at the base of their capability to respond precisely to appropriate stimuli with differentiative behaviour. Understanding this essential principle of multicellular life; i.e., the regulation of cell identity and fate, is one of the most important fields of research in modern cell biology, primarily due to its impact on the development of new therapeutic approaches in regenerative medicine. Such knowledge can directly benefit stem cell bioengineering by leveraging the SC plasticity and control over SC behaviour for the application in tissue engineering, patient-specific disease modelling and cell therapies ( Tewary et al., 2018 ).

Conclusions

In recent years there has been a fascinating expansion of our knowledge about the interplay between mechanotransductive signalling and chromatin regulation, and how this impacts on multi- and pluripotent stem cell dynamics, which we try to highlight in this review.

However, what shapes the life of a cell and its identity, from the outside (biophysical and structural cues of the cellular microenvironment) and from the inside (nuclear and chromatin organisation) and how it is connected (mechanotransduction and epigenetics) are highly relevant biological issues that are yet far from being understood in detail. Starting from the stem cell/microenvironment interface, a much more detailed understanding of the nanoscale events in this interface is necessary to unravel 1) what the SC perceives of the biophysical nature and the 3D adhesion site configuration and 2) how the immanent nanoscale information is interpreted and converted, through force-based actions, into a remodelling at the level of the IACs, cell/cell adhesions, cytoskeleton and nucleus.

Abstract

Developmental prosopagnosia (DP) is a condition that indicates the inability to recognize individuals by their faces from birth, without any history of brain damage. The assessment of face recognition ability and diagnosis of DP involve the use of face tests such as the Cambridge Face Memory Test (CFMT) and the Cambridge Face Perception Test, along with self-reported measures like the 20-Item Prosopagnosia Index (PI20). Face recognition accuracy is affected by anxiety. However, previous studies on the relationship between face recognition ability and anxiety have not used the PI20 measure. This study aimed to investigate the relationship between self-reported measures of face recognition ability and anxiety tendencies among healthy young individuals for DP diagnosis and its implications. We used a face recognition test, involving the PI20, CFMT, Visual Perception Test for Agnosia–Famous Face Test (VPTA–FFT), and State-Trait Anxiety Inventory (STAI). We assessed the performance of 116 Japanese young adults (75 females, median age of 20.7 years, with a standard deviation of 1.2). Subsequently, we conducted a statistical analysis to examine the relationship between the outcomes of the face recognition tests and STAI scores using Pearson correlation analysis and single correlation coefficients. The results showed a positive correlation between state anxiety and PI20 (r = 0.308, p = 0.007), and a weak positive correlation was also observed between trait anxiety and PI20 (r = 0.268, p = 0.04). In contrast, there was no correlation between CFMT and VPTA–FFT with respect to STAI. The results of the hierarchical multiple regression analysis also suggested that the correlation between the performance on the PI20 (self-report) and objective measures of face recognition performance (the CFMT and the VPTA–FFT) are driven by differences in anxiety. This study is the first to explore the relationship between face recognition abilities and anxiety using the PI20 self-report measure. There are implications for future research on the diagnosis of DP and the relationship between anxiety and face recognition.

Introduction

Face recognition ability enables individuals to differentiate and identify faces, playing a crucial role in interpersonal recognition and everyday communication. Clinical and functional imaging studies have highlighted that brain lesions, particularly in regions such as the fusiform gyrus, can lead to face recognition impairment. In recent years, there has been a growing interest in the field of face recognition research regarding developmental prosopagnosia (DP). DP refers to a condition in which individuals experience lifelong impairments in face recognition despite possessing normal visual and intellectual capabilities since birth. Clinically, there is no indication of overt central nervous system disorders, and neuroimaging studies also reveal the absence of organic brain lesions (Bate & Tree, 2017; Behrmann & Avidan, 2005; Cook & Biotti, 2016; Duchaine & Nakayama, 2006a). Epidemiological studies in Europe and Asia have reported a prevalence rate of approximately 1.9 %–2.9 % of the population (Bowles et al., 2009; Kennerknecht et al., 2006; Kennerknecht et al., 2008). People with DP encounter challenges and psychosocial difficulties in their interpersonal interactions due to impaired face recognition (Yardley et al., 2008). Early diagnosis and support are crucial, especially before adulthood and entering the workforce.

Currently, diagnosing DP presents challenges due to the absence of established strict objective criteria or biological markers (Barton & Corrow, 2016; Susilo & Duchaine, 2013). Previous studies have revealed ambiguous criteria for diagnosing DP and differentiating it from conditions other than DP in face recognition tests (Bate & Tree, 2017; Dalrymple & Palermo, 2016). Dalrymple and Palermo (2016) provided guidelines that define DP as objectively poor performance on face memory tests and a subjective feeling of repeated face recognition failures in daily life. The authors emphasized the importance of using questionnaires and interviews to assess face recognition difficulties in daily life and highlighted the limitations of relying solely on questionnaires for DP diagnosis, as individuals with DP may lack accurate insight into their own face recognition abilities.

Conclusions

The present study is the first to investigate the relationship between self-reported face recognition abilities and anxiety in young, healthy Japanese individuals using the self-perception face recognition test PI20. The findings indicated that unlike the objective face recognition tests CFMT and VPTA–FFT that showed no association with anxiety, the self-perception test scores may be influenced by state anxiety. Self-reporting, at least in its current form, provides limited insights into predicting face recognition performance in young individuals and diagnosing DP. Therefore, self-reporting is insufficient to evaluate face recognition abilities in young individuals, and DP cannot be diagnosed solely based on self-perception tests. It is necessary to combine self-perceived indicators of face recognition impairment with other perception-based face recognition function tests and consider the presence and extent of anxiety tendencies. Our findings have significant psychological implications for understanding face recognition impairments, DP diagnosis, and clinical practices. In the future, expanding research to investigate the interaction between facial and expression recognition abilities and anxiety is expected to enhance the accurate diagnosis and support for young individuals with facial recognition impairments.

Abstract

Background. The latest Movement Disorder Society (MDS) diagnostic criteria require a good and sustained response to medication to get a diagnosis of Parkinson’s disease, PD. Objective. The aim of this study was to evaluate levodopa response in a group of patients with probable PD, diagnosed by movement disorder specialists. Methods. An acute levodopa challenge test (LDCT) was performed after pausing the dopaminergic medication for 6 half-times. The motor part of the Unified Parkinson’s Disease Rating Scale was performed in the OFF-state and after LDCT (ON). A good effect was defined as >30% improvement. A video-protocol was used to secure standardized motor examination with blinded assessments of the UPDRS-III OFF and ON. An age-matched group of control subjects (CS) was included but did not go through LDCT. All participants were evaluated with Montreal Cognitive Assessment (MoCA) and Beck’s Depression Inventory (BDI). Results. In the statistical analysis, 37 patients were included. Twenty-one patients showed an improvement ≤30%, while 16 patients showed an improvement >30%. LDCT showed an overall mean improvement of 27.3% of motor UPDRS. In 43.2%, there was a discrepancy between the effect seen with the LDCT and the patients’ self-perceived medicine evaluation. Patients with PD had a significantly lower MoCA score and more depressive symptoms compared to CS. Conclusions. We showed an acute effect of levodopa using LDCT that was around 30% improvement. While it lends support to the use of this limit in the MDS diagnostic criteria, an acute effect of less than 30% should be considered acceptable in some patients. Our study highlights a discrepancy in the objective measure of medicine effect on motor symptoms and the patient’s subjective evaluation.

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, causing severe disability with increasing prevalence. A diagnosis of PD is based on the motor manifestations: bradykinesia, rigidity, and tremor, and clinical symptoms related to the loss of dopamine. In PD, these symptoms of parkinsonism are related to a neurodegenerative pathological process involving misfolding and aggregation of α-synuclein and formation of inclusion bodies, Lewy bodies, primarily in dopaminergic neurons. A diagnosis of PD is clinicopathological and requires both this pathological hallmark as well as the clinical phenomenology. In 2015, the Movement Disorder Society (MDS) put forward updated clinical diagnostic criteria for PD to increase early diagnostic accuracy in patients with Lewy body pathology Parkinson’s disease [1]. Dopaminergic neuronal loss in addition to Lewy body formation is central in the pathology of PD. In the diagnostic criteria from 2015, the importance of this pathological hallmark is emphasized even more than in earlier diagnostic criteria [2], through suggestion of operational criteria including (i) support by objective measurement of effect on motor symptoms showing a >30% improvement with dopaminergic medication in the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS-III), (ii) a clearly documented history of marked changes with medication from the patient or the caregiver, and also that (iii) lack of sufficient motor improvement should be an exclusion criterion [3].

While the diagnostic criteria of PD from MDS have been validated against expert clinical diagnosis and the United Kingdom Brain Bank criteria from 1988 [4], the clinical importance of having this definition of the effect of medication in a movement disorder clinic may still be more thoroughly evaluated.

Treatment with levodopa (L-dopa) is the most efficient dopaminergic therapy and the golden standard treatment for PD [1]. An evaluation of dopaminergic effect is therefore necessarily based on treatment with L-dopa. To evaluate the treatment effect in an objective manner, the standardized acute levodopa challenge test (LDCT) can be used to assess motor symptoms both OFF and ON medication to evaluate the L-dopa response. Besides using LDCT in a diagnostic approach, the acute LDCT protocol has been described and used in the measurement of disease progression [5]. In addition, it has been widely accepted as an evaluation of levodopa effect as a preoperative evaluation before deep brain stimulation of the subthalamic nucleus (STN-DBS) [6].

Conclusion

We have performed a clinically relevant evaluation of levodopa response in a group of patients with PD with both a self-reported good and poor L-dopa response. An acute LDCT was performed as an objective measure, but a surprisingly large discrepancy was found between the subjectively reported usual response and the acute effect. As patients all otherwise had a diagnosis of PD, a good effect should be found for both the subjective and objective evaluation in accordance with diagnostic criteria. Our study sheds light on the importance of questioning the reported effect when making a diagnosis. The mean LCDT was close to 30% in most cases, but our study indicates that an acute effect of less than 30% should sometimes be expected.

In conclusion, this study showed that the LCDT can be used as a diagnostic support and that it is a valuable tool in addition to the self-reported effect from the patient. But also, that conclusions based on an acute effect of less than 30% should be evaluated with caution, as this was the case in 56.8% of the patients with PD in our study.

Abstract

The current paper aimed to analyze quantitatively the trends of four major schools of thought in scientific Psychology (neuroscience, cognitivism, behaviorism, psychoanalysis) and their intersections, covering the period from 1979 to 2020. We utilized a rigorous methodology across three distinct sources: Mainstream Psychology (MP), Highly Influential Journal (HIJ), and non-English papers (NEP). Our findings align with previous research in two aspects: psychoanalysis and behaviorism have significantly declined, cognitivism remains a prominent trend. However, we deviate from prior studies by recognizing that neuroscience may be considered the most influential trend and that trends exhibit less linearity than previously assumed. We also acknowledge the significance of NEP, which manifest an independent pattern as compared to the other sources and that may reveal what happens in the “periphery” of Psychology. It is noteworthy that NEP demonstrated a still lively contribution from psychoanalysis. Our study also highlights the insularity and lack of cross-fertilization among psychological subdisciplines, despite the widespread claims to the contrary. It eventually supports the inference that scientific Psychology is a non-paradigmatic or pre-paradigmatic discipline, pointing out the dominance of applied psychology and confuting the notion of overarching “grand theories”.

History of the empirical analyses of trends in psychology

The study conducted by Friman et al. (1993) was one of the pioneering empirical investigations into the trends of subdisciplines within the field of Psychology. The authors specifically focused on psychoanalysis, behaviorism, and cognitivism during the years 1979–1988, utilizing data obtained from the Social Science Journal of Citation Reports (SSJCR). In their research, the authors selected four influential journals that represented each subdiscipline, taking into consideration various criteria, including a relatively high Impact Factor (IF)1 (for further details see Friman et al., 1993, pp. 659-660). For instance, Cognitive Psychology, Cognition, Journal of Experimental Psychology: Learning, Memory, and Cognition, and Memory & Cognition, aligned with the cognitive approach.

In the study conducted by Friman et al. (1993), the four selected journals representing each sub-discipline were examined using four different indexes: IF, Immediacy Index (II),2 citation number (the number of times the journal has been cited during a given year), and source items (the number of citable items the journal has produced during a given year). These indexes were calculated for each journal on an annual basis, and then averaged across the four journals to obtain single indexes for each sub-discipline. The three indexes were eventually plotted against each other. The main finding of the study indicated a significant increase in prominence for the cognitive school of thought. However, it was observed that the citation numbers and source items for behaviorism and psychoanalysis, although lower than those of cognitivism, were not substantially inferior. Despite the rise of the cognitive school, the study did not provide evidence for a clear-cut Kuhnian paradigmatic shift. Additionally, when considering the broader context of the social sciences, all three sub-disciplines (cognitive, behaviorism, and psychoanalysis) performed relatively well in comparison to other indexed journals in the SSJCR.

Conclusion

Taking a more speculative and substantial perspective on the history of Psychology, it can be inferred from the current data that over the past 40 years, the major scientific discourses have predominantly centered around the brain. Many recent studies (Bittermann & Fischer, 2018; Tracy et al., 2004; Yeung, Goto, & Leung, 2017; Wieczorek et al., 2021) suggest an increasing importance in neuroscience within Psychology and more widely across all natural sciences, and Benjafield (2020) highlights how the vocabulary of Psychology is more dependent on Biology than vice versa. These observations suggest an imbalance favoring biologically-based theories over emergentist/spiritualistic ones, although it does not necessarily imply a complete endorsement of materialism by neuroscientists. Rather, it might signify only an informal inclination towards biologically-based explanations. It is noteworthy that psychological researchers rarely adopt a clear ontological standpoint on “mind” and “behavior” and generally avoid extensive engagement with philosophical and theoretical issues (Henriques, 2011; Zagaria et al., 2020).

All things considered, the enduring and relatively stable patterns observed over a 40-year period are indicative of the robustness and vitality of Psychology as a discipline. These patterns demonstrate that the theoretical assumptions regarding the mind have exhibited relative stability over an extended duration.

Abstract

Oral cavity stem cells (OCSCs) have been the focus of intense scientific efforts due to their accessibility and stem cell properties. The present work aims to compare the different characteristics of 6 types of dental stem cells derived from the oral cavity: dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), bone marrow mesenchymal stem cells (BMSC), and gingival mesenchymal stem cells (GMSC). Using immunofluorescence and real-time polymerase chain reaction techniques, we analysed the cells for stem cell, differentiation, adhesion, and extracellular matrix markers; the ability to proliferate in vitro; and multilineage differentiation potential. Markers such as vimentin, CD44, alkaline phosphatase, CD146, CD271, CD49f, Oct 3/4, Sox 9, FGF7, nestin, and BMP4 showed significant differences in expression levels, highlighting the heterogeneity and unique characteristics of each cell type. At the same time, we confirmed that all cell types successfully differentiated into osteogenic, chondrogenic, or adipose lineages, with different readiness. In conclusion, our study reveals the distinct properties and potential applications of various dental-derived stem cells. These findings contribute to a deeper understanding of OCSCs and their significance in future clinical applications.

Introduction

Bone marrow mesenchymal stem cells (BMSCs) exhibit high proliferation ability and multilineage differentiation potential. They were the first mesenchymal stem cells (MSCs) to be described, isolated from adults’ bone marrow aspirate.1 They have been extensively researched in human and animal model systems using in vivo and in vitro cell cultures. Further, they have bridged the divide and are integrated into various trials for clinical applications, with mixed success.2,3 BMSCs are not easily accessible, and an invasive procedure is required. Therefore, further research in the field, aiming at identifying alternative stem cell sources, has led to the discovery of oral cavity stem cells (OCSCs).

Currently, several different types of OCSCs are well known, including dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), dental follicle stem cells (DFSC), and gingival mesenchymal stem cells (GMSC).

Conclusions

This analysis of oral cavity–derived stem cells has exposed distinct and specific expression patterns of surface markers, ECM components, ECM remodelling enzymes, collagen genes, integrins, and differentiation potential. These findings may provide insights into the functional properties of these cell populations. Оur study aims to uncover the nuanced characteristics specific to each distinct cell type. Through experimentation and analysis, we anticipate to not only understand their individual functionalities but also gain deeper insights into their collective behaviour. Understanding both their shared characteristics and distinct attributes is an important step in using their regenerative potential in various tissue repair and regeneration contexts, thereby advancing the field of regenerative medicine and tissue engineering. By contributing meaningfully to the advancement of knowledge in regenerative medicine and tissue engineering, we aspire to pave the way for transformative breakthroughs in health care.

Abstract

Background
General practitioners play a pivotal role in the diagnosis attention-deficit/hyperactivity disorder (ADHD) in adults. This systematic review aims to determine the effectivity and feasibility of screening tools for ADHD in adults in primary care.

Method
A literature search was performed in PubMed, Cochrane Library, Ovid, ERIC, PsycInfo, PSYNDEX and Embase in November 2022. Sensitivity and specificity were considered as primary outcomes. Further psychometric properties, feasibility in general practice as well as digital practicability were evaluated as secondary outcomes. Risk of bias was assessed via QUADAS-2/C. A narrative data synthesis and meta-analysis was performed (PROSPERO: CRD42022374597).

Results
A total of fifty-eight studies were included in data analysis. These studies referred to eighty-four various screening tools. ASRS-6 (DSM-V), WURS-25, CAARS-s:sV and TRAQ10 are suitable instruments for screening of ADHD in adults in primary care. The highest test accuracy was shown by ASRS 6 (DSM-V) (Sensitivity=0.83 [0.67–0.92], Specificity=0.87 [0.93–0.8], AUC=0.92, I2=8.6–12.3 %).

Limitations
Included studies used rating scales as reference standard. Some studies compared study groups to control groups with an unknown ADHD status and there is a large degree of heterogeneity between the populations. Some studies referred to the best-balanced results of sensitivity and specificity under a certain cut-off, that has not been determined before.

Conclusion
Feasibility studies are needed to provide more evidence for WURS-25 and CAARS-s:sV. The determination of sufficient cut-offs is important, to improve the identification of ADHD in adults by general physicians.

Introduction

Attention-deficit/hyperactive disorder (ADHD) according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) and hyperkinetic disorder (F90) or attention deficit without hyperactivity (F98.8) according to the International Classification of Diseases, editions 10 and 11 (ICD-10/11)) is commonly known as a childhood disorder which is characterized by altered hyperactivity, inattention and impulsivity (Drechsler et al., 2020). These symptoms persist until adulthood in about 50 % of all diagnosed patients (Sibley et al., 2017, 2022). Moreover, patients show characteristic features, which include executive dysfunction, disorganization and emotional distress, leading to an impairment of their daily lives (Barkley, 1997; Wender, 1998). Common comorbidities are depression, borderline personality disorder, social phobia, anxiety, or substance abuse (Fayyad et al., 2017; Kessler et al., 2006). Although a prevalence of approximately 2–3 % of ADHD in adults is estimated, only 0.2–0.4 % are actually diagnosed in Germany (Fayyad et al., 2017; Bachmann et al., 2017; de Zwaan et al., 2012). A possible reason seems to be a gap in medical care for young adults in a time of transition after leaving the pediatric setting (Eklund et al., 2016; Robb and Findling, 2013). Moreover, ADHD might be masked by other psychiatric symptoms and comorbidities (Retz et al., 2013). A missing or failed diagnosis prevents access to optimal medical care in the form of an evidence-based treatment of affected adults. General practitioners are considered to act as so-called „gatekeepers“, a role that is characterized by the initial identification of patients (Kwon et al., 2023; French et al., 2020). Consequently, there is a distinct need for appropriate diagnostic tools in primary care, as has already been identified in relevant guidelines (Eom and Kim, 2023; National Institute for Health and Care Excellence: Guidelines, 2018). There are many different screening tools, which differ in relevant aspects of the disorder. Some screening tools evaluate childhood symptoms, whereas others focus on current adult symptoms. Some screening tools are based on DSM-5 criteria, others on Utah criteria or no specified criteria. They differ in time or way of application, number of items, and scoring methods. For example, the choice of cutoff scores in ADHD screening tools directly influences clinical decision-making, including the initiation of treatment interventions. A higher cutoff score may exclude individuals who, despite exhibiting significant symptoms, do not meet the stringent criteria, potentially denying them access to necessary interventions. Conversely, a lower cutoff score could lead to the inclusion of individuals with mild symptoms, leading to over-treatment. The variability in cutoff points complicates the determination of treatment eligibility, potentially affecting the efficacy and efficiency of ADHD management strategies. Until, there is no comprehensive overview of validated studies including a quantitative meta-analysis (Taylor et al., 2011). Therefore, the aim of the study was to evaluate screening tools for ADHD in adults, considering sensitivity, specificity and feasibility for primary care.

Conclusion

Our findings show that screening tools as the ASRS-6 (DSM-V), the WURS-25, the CAARS-s:sV and the TRAQ10 are suitable instruments for screening of ADHD in adults in primary care due to their high validity and perceived feasibility in this setting. The best evidence exists for the ASRS-6, which was included in our meta-analysis. For more evidence concerning feasibility of the WURS-25 as well as the CAARS-s:sV, which also were part of the meta-analysis, feasibility studies are required. Regarding other tests like the TRAQ10 with equivalent promising results but insufficient options of comparison there is a need of further validation studies to create more evidence in that part. The determination of cut-offs is of great importance since it affects the ability of a screening tool distinguishing between real and false positives respectively negatives. Further research is required to identify the optimal cut-off of the different tests for a general population sample as we find it in primary care. Hence, the identification of ADHD in adults by general physicians would be improved without leading to increased misdiagnoses.

Abstract

Background
Progress has been achieved in many fields in understanding the biological mechanisms of depression, including genome-wide association analysis, neurotransmitter system function, brain regions and neural networks, inflammatory response, neuroplasticity, neuroimaging, and neuro electrophysiology. These progresses provide a reliable basis for developing the medical and physical therapies for depression. However, the current treatments developed from biological mechanisms can only address less than 60% of depressive symptoms and have limited efficacy in improving social functioning and reducing recurrence. Studies have explored the non-biological mechanisms of depression in mental fields. These progresses are helpful to develop more interventions that could alleviate depressive symptoms, improve functional impairments, and reduce recurrence, thereby promoting a more comprehensive recovery in depressed patients. However, there is not a systematic and deep review to highlight the non-biological mechanisms of depression.

Methods
This study summarizes the recent progress in the non-biological fields of depression by searching publications on human studies in PubMed, PMC, and Google Schooler with exclusion of animal studies.

Results
This study reviews the intergenerational transmission characteristics, the relationship between depression and emotional trauma, cognitive deficit, relationship impairment, self-function, sense of the meaning of life, motivation deficit, and psycho-rationality of depression.

Conclusions
This study was clarified the non-biological mechanisms and characteristics of depression and provided a theoretical basis for the development of non-drug interventions.

Introduction

To date, studies on the pathogenesis of depression are mainly focus on its biological mechanisms (Miao & Chang, 2021), including studies on epigenetic alterations, genome-wide association, neurotransmitter system, brain regions and neural networks, inflammatory responses, neuroplasticity, neuroimaging, and neuro electrophysiological changes (Li et al., 2021). The outstanding contributions of these studies provide a theoretical basis for pharmacotherapy and physical therapy of depression (Li et al., 2019). However, the current treatments developed from biological mechanisms can only relieve 58% of depressive symptoms (Ormel et al., 2019). Moreover, these current pharmacotherapy and physical therapy have limited efficacy in improving prognosis and social function, as well as reducing relapse rates (Cieślik et al., 2020). The cognitive behavioral therapy has been shown to be highly effective in treating depression but has limited impact on generational deficits and trauma-related emotional responses in the symptomatic components of depressive symptoms (Johnsen, T. J., & Friborg, O. 2015). The eye movement desensitization and reprocessing therapy has shown some positive outcomes in helping individuals to reprocess traumatic memories of some emotional traumas, but it is not appropriate for traumatized populations of all backgrounds and can exacerbate symptoms in some populations. Therefore, its limitations and side effects need to be considered (Shapiro, F. 2014). Thus, exploration of new mechanisms and subsequent development of new treatments is an urgent need for patients with depression.

Results

3.1. Non-biological transgenerational transmission of depression
Intergenerational transmission of pathological psychology refers to the phenomenon that psychological disorders or problems presented in the previous generation can reappear in the next generation, or that the behavior or psychological trauma of the previous generation causes mental and psychological problems in the next generation. These problems may span generations and manifest in different ways and degrees (Cooke et al., 2019). In recent years, evidence on the intergenerational transmission of depression has been accumulated. In the biomedical field, family and twin studies have repeatedly validated that the intergenerational transmission of depression is often a result of gene-mediated genetic disorders or epigenetic inheritance (Goodman, 2020, Park et al., 2019). However, the non-biological transgenerational mechanisms of depression have also attracted attention recently (Gotlib et al., 2020).

More and more non-biological transmissions have been observed, while the intergenerational phenomenon of depression and its transmission ways have different explanations (Hentges et al., 2021). For example, parental depression may be transmitted to the next generation through multiple pathways: intergenerational transmission of trauma (Hankerson et al., 2022); intergenerational damage to emotions, self-esteem, and cognition; family culture; parenting style; and behavioral consequences etc. (Kang et al., 2021, Risi et al., 2021, Kujawa et al., 2020, Johnco et al., 2021). These transgenerational mechanisms may indirectly influence the biological changes that evolve into the symptoms of depression (Allison et al., 2023). In the intergenerational transmission of depression, offspring may not inherit the symptoms of depression, but instead display a variety of psychological dysfunctions a variety of psychological dysfunctions, including a tendency to react negatively to emotions (Israel & Gibb, 2024), a state of self-esteem hypersensitivity, cognitive biases, and excessive self-focus (Woody et al., 2022). In addition, offspring may also display relationships with alienation, control, and unclear boundaries (Wei et al., 2023), and even the characteristics of illness that appear in early adulthood or suicidal tendencies (Gijzen et al., 2021).

Abstract

The newly constituted National Multiple Sclerosis (MS) Society (NMSS)of the United Arab Emirates (UAE), set up a scientific committee to create a MS disease modifying treatment (DMT) guideline for UAE. The committee considered several unique features of the MS community in UAE including large number of expatriate population, wide variations in health insurance coverage, physician and patient preferences for DMT. The overall goal of the treatment guideline is to facilitate the most appropriate DMT to the widest number of patients. To this end it has adapted recommendations from various health systems and regulatory authorities into a pragmatic amalgamation of best practices from across the world. Importantly where data is unavailable or controversial, a common sense approach is taken rather than leave physicians and patients in limbo. The committee classifies MS into subcategories and suggests appropriate treatment choices. It recommends treatment of RIS and CIS with poor prognostic factors. It largely equates the efficacy and safety of DMT with similar mechanisms of action or drug classes e.g. ocrelizumab is similar to rituximab. It allows early switching of treatment for unambiguous disease activity and those with progression independent of relapses. Autologous hematopoietic stem cell transplantation can be offered to patients who fail one high efficacy DMT. Pragmatic guidance on switching and stopping DMT, DMT choices in pregnancy, lactation and pediatric MS have been included. It is expected that these guidelines will be updated periodically as new data becomes available.

Introduction

The United Arab Emirates (UAE) is home to about 10 million people, of which one million are Emirati citizens. UAE is considered a country with medium prevalence for Multiple Sclerosis (MS). Estimates of prevalence are crude and range from 57/100,000 increasing to 64/100,000 when age-standardised (Inshasi & Thakre, 2011, Schiess et al., 2016, Mohammed, 2016). MS is more common in native Emirati people than in a mixed population of Emiratis and expatriates with the majority having relapsing MS (Schiess et al., 2016).

All neurologists (not necessarily MS specialists) can manage MS. Primary care systems are not well established in UAE and patients self-refer to hospitals. Onward referrals to larger centres with expertise is uncommon, unless patients themselves chose to do so. Most MS Disease modifying treatments (DMT) are available in UAE. While UAE has a medical regulatory authority, its role has not yet extended into appraisals of individual medicines or cost effectiveness. Therefore, adoption of recommendations by the Food and Drug Administration(FDA) or European Medicines Agency (EMA) is the standard practice. There is presently no guideline for MS DMT in UAE. So, Neurologists use FDA, EMA approved drugs that are available in UAE as per their preferences and guided by the American Academy of Neurology (AAN), European Academy of Neurology (EAN) and Middle East North Africa Committee for Treatment and Research in MS (MENACTRIMS) guidelines (Yamout et al., 2024). This pragmatic approach combined with affordability (UAE per capita GDP is 44,315 USD compared to the EU 38,411 USD) (GDP comparision UAE and EU) has helped the quick introduction of new drugs in UAE once approved in North America or Europe.

Conclusions

MS is a complex chronic disease with high risk of long-term disability. In this broad and yet specific DMT guideline we have tried to put together pragmatic amalgamation of best practice from across the world that takes into account UAE’s unique situation and demography. The overall goal of the treatment guideline is to facilitate the most appropriate DMT to the widest number of patients and to facilitate emerging treatments earlier. Where data is unavailable or controversial, a common sense approach has been adopted rather than leave physicians and patients in limbo. It is expected that these guidelines will be updated periodically as new data becomes available.

Abstract

Parkinson’s disease is a prevalent neurodegenerative disorder that is clinically identified by motor deficits. Its pathogenesis remains unclear and current treatments cannot reverse disease progression. Mounting evidence suggests that cellular senescence plays a crucial part in the development of Parkinson’s disease. The analysis of genes related to aging in Parkinson’s samples using bioinformatics has not been conducted so far. This study identified differentially expressed senescence genes using bioinformatics approaches and found genes RASL11B and PRRG1 to be highly correlated with Parkinson’s, suggesting their potential as diagnostic and therapeutic targets. The miR-20 family of miRNAs may participate in Parkinson’s pathogenesis by regulating these genes. Examining senescence genes within a senescence network framework, this study pioneers the investigation of their involvement in Parkinson’s disease. It establishes the theoretical groundwork and identifies potential targets for the development of innovative diagnostic and therapeutic approaches focused on senescence. The present research reveals the important function of aging processes in the development of Parkinson’s disease, enabling the advancement of novel diagnostic and therapeutic approaches for Parkinson’s that focus on mechanisms related to aging.

Introduction

Parkinson’s disease (PD) is a degenerative disorder of the nervous system that is identified by the degeneration of dopaminergic neurons in the substantia nigra region of the brain. This degeneration causes motor symptoms including tremors, stiffness, and slow movement. The condition affects approximately 2%–3% of individuals who are 65 years old and above (Poewe et al., 2017), with an annual incidence rate ranging from 10 to 18 per 100,000 people (Van Den Eeden et al., 2003). Moreover, the prevalence rate among individuals in my country who are 65 years old and above is recorded at 1.7% (Chen et al., 2016). The development of PD is intricate, encompassing interactions among hereditary and ecological elements (Bellou et al., 2016; Hernandez et al., 2016). Nonetheless, recent studies suggest that the pathogenic mechanisms of PD could be associated with cellular senescence (Sahu et al., 2022). Cellular senescence refers to a state of irreversible cell cycle arrest that is activated by different stressors, including telomere shortening (Hunt et al., 2015; Kuszel et al., 2015), DNA damage (Bai, 2015; Bai et al., 2015), and oxidative stress (Blacker and Duchen, 2016). Senescent cells display various phenotypic alterations, such as modified gene expression, release of proinflammatory substances, and reduced sensitivity to growth factors (Hayflick, 1965). The buildup of aging cells has been linked to diseases associated with aging, including cancer, heart disease, and neurodegenerative disorders. Recent studies suggest that the buildup of aging cells might contribute to the development of PD. In the brains of individuals with PD, researchers have observed aging dopaminergic neurons, while aging astrocytes were discovered to release proinflammatory cytokines that contribute to neuroinflammation (Franceschi et al., 2007; Chung et al., 2009). Furthermore, it has been demonstrated that aging cells can hinder the functioning of mitochondria (Reeve et al., 2013), which is believed to have a crucial impact on the development of PD. Hence, focusing on aged cells is seen as a hopeful path that may hinder or ease the beginning and advancement of PD by targeting the aged characteristic. The advancements in microarray technology and bioinformatics have significantly assisted the progress of biomedicine. At present, these bioinformatics examinations offer insightful hints to comprehend the origin of PD from various perspectives. Nevertheless, the precise molecular mechanisms connecting cellular senescence to PD pathology are still unknown. Consequently, our objective in this research is to examine PD-related GEO datasets from the standpoint of SAGs. The identification of SADEGs involved limma testing, WGCNA, and the intersection of 1302 genes related to senescence and senescence-associated genes. GO and GSEA were used to determine the possible biological roles and pathways of SADEGs. Next, the identification of hub genes linked to the progression of PD was carried out using SVM-RFE, LASSO logistic regression, and RF. Furthermore, we investigated the associations between the central genes and Parkinson’s disease. In the end, the validation set was used to confirm the expression levels of four central genes.

Conclusion

To summarize, we have discovered and confirmed two genes (RASL11B and PRRG1) that are strongly linked to PD and are involved in the process of senescence. The results of our study indicate that these genes could have significant functions in the onset and advancement of PD pathology. Our study reveals the participation of RASL11B and PRRG1 in PD, offering fresh perspectives on their potential as biomarkers for early detection and monitoring of the disease. Additional investigation is necessary to explore the mechanisms by which these genes contribute to the development of PD, as it has the potential to unveil novel therapeutic targets. In general, our discovery of the connections between genes related to aging and PD signifies a significant progress in comprehending the causes and development of PD.

There are some limitations to our study:Although we validated our results with other datasets, there may be some bias in our interpretation due to the relatively small sample size and data from mRNA expression. In future work, we intend to perform ELISA experiments (at the protein level) to validate the diagnostic role of these two SADEGs in larger sample sizes.

Summary

Background
Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.

Methods
Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.

Findings
Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95–1·01), stroke (1·01, [0·97–1·05]), or all-cause mortality (0·99, 0·95–1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations.

Interpretation
Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status.

Funding
British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Introduction

Vitamin D is an essential nutrient obtained from sunlight, dietary intake, and supplementation.1 Observational epidemiological studies have consistently found that low concentrations of circulating 25-hydroxyvitamin D (25[OH]D), a metabolite used as a clinical indicator of vitamin D status, are associated with an increased risk of cardiovascular disease and all-cause mortality, as well as other chronic diseases.2,  3 However, several large randomised trials of vitamin D supplementation have reported null results,4,  5,  6 casting doubt on the observational evidence. However, as trials have typically recruited participants irrespective of baseline 25(OH)D concentration, they have had limited power to test supplementation effects in subgroups with low 25(OH)D concentrations.7

An efficient approach for assessing the potential causal effect of vitamin D supplementation is Mendelian randomisation. Mendelian randomisation uses genetic variants specifically related to a particular exposure to compare genetically defined population subgroups with different average levels of the exposure. The independent segregation of alleles at conception means that these genetically defined subgroups should not differ systematically with respect to confounding variables, creating a natural experiment analogous to a randomised trial.8 Therefore, Mendelian randomisation analyses can provide more reliable insights into causal relationships between risk factors and disease outcomes than conventional observational analyses. Previous Mendelian randomisation analyses have reported null associations of genetically predicted 25(OH)D concentrations with coronary heart disease9,  10 and ischaemic stroke.11,  12 An inverse association has been observed between genetically predicted 25(OH)D and all-cause mortality.13 Null findings have been observed for several further outcomes, including other cardiovascular diseases and cancers.14

Results

386 406 participants from the four studies were included in genetic analyses (table 1), including 33 546 people who had coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died, and 500 962 participants were included in observational analyses (appendix 3 pp 11–13). Mean age of participants included in the genetic analysis ranged from 54·8 years (SD 9·4) to 57·5 years (12·9), with similar numbers of men and women in each study, and the mean season-shifted 25(OH)D concentrations (corresponding to an autumn measurement) were 54·5 nmol/L (SD 19·6) in UK Biobank, 46·9 nmol/L (16·4) in EPIC-CVD, and 53·8 nmol/L (25·9) in the Copenhagen studies. Mean 25(OH)D estimates did not notably differ by assay type (appendix 3 p 21). The focused genetic risk score explained 4·7% of the variance in 25(OH)D concentrations in UK Biobank study, 5·8% in EPIC-CVD, and 1·8% in the Copenhagen studies. This genetic risk score was not associated with a range of cardiovascular risk factors in UK Biobank, except for BMI and HDL cholesterol, although these associations were small (appendix 3 p 22). The genome-wide score was strongly associated with LDL cholesterol and triglycerides (appendix 3 p 23), and so Mendelian randomisation estimates using this score are unreliable.