Abstract

Background
People with diabetes have an increased risk of heart failure (HF), compared to those without diabetes. However, no comprehensive systematic review and meta-analysis has explored whether these associations could differ in relation to prevalent cardiovascular disease (CVD).

Aims
To estimate the association between diabetes and incident heart failure (HF), compared to without diabetes, in individuals with and without CVD.

Methods
PubMed, Scopus, and Web of Science were searched for observational cohort studies from the earliest dates to 22nd March 2023. A random-effects model calculated the pooled relative risk (RR).

Results
Of 11,609 articles, 31 and 6 studies reported data in people with type 2 diabetes (T2D) and type 1 diabetes (T1D) respectively. Individuals with T2D had an increased risk of HF irrespective of CVD prevalence: 1.61 (95% CI: 1.35–1.92) in those with CVD; 1.78 (1.60–1.99) without CVD; and 2.02 (1.75–2.33) with unspecified CVD prevalence. Meta-regression did not identify a significant difference comparing HF risk in T2D individuals with vs. without CVD (p = 0.232).

Conclusion
People with T2D, compared to those without diabetes, have similar increased risk of HF, regardless of CVD prevalence. Strategies proven to lower HF risk in T2D individuals should be prioritized for those with and without CVD.

Introduction

Diabetes mellitus and heart failure (HF) tend to exist as common comorbid conditions [1], with approximately 4.3 to 28 % of HF individuals with prevalent type 2 diabetes (T2D) and 12–57 % of T2D individuals presenting with HF [2]. People with diabetes also have an increased risk of HF, which subsequently increases their risk of hospitalizations [3], [4] and mortality [5], [6] to further burden global economic and healthcare resources [7]. Nearly 537 million adults are currently living with diabetes world-wide, estimated to rise to 643 million by 2030 [8]; HF currently affects 64.3 million people globally [9], predicted to rise by 50 % in the next 20 years [10]. Hence, early prevention and management strategies to lower HF risk in individuals with diabetes is of public health importance [11], [12]. This is further reinforced in evidence showing HF as the most common initial presentation of cardiovascular disease (CVD) in people with diabetes [13].

A previous meta-analysis from 2018 [14] showed that persons with diabetes have an increased risk of HF, relative to without diabetes (relative risk, RR: 2.06, 95 % confidence interval, CI: 1.73 to 2.46). However, this study pooled estimates from heterogeneous study designs (e.g., case-control and cohort), which could have led to biased estimates. To address this limitation, a recent 2020 meta-analysis [15], exclusively using data from observational cohort studies, reported that individuals with diabetes have an increased risk of new-onset HF, relative to without diabetes (RR: 2.14; 95 % CI: 1.96 to 2.34). However, the author’s included studies that did not adjust for at minimum age and sex, which could have led to biased results. The study also found an attenuated association when restricting the population to individuals with prevalent coronary heart disease (CHD) (RR: 1.94, 95 % CI: 1.77 to 2.12) [15]. It remains unclear whether, and to what extent, the association between diabetes and incident HF could differ in populations with and without broad CVD.

Results

3.1. Study characteristics
Of the 11,609 studies, 31 articles [6,13,22–50] consisting of 34 cohorts for T2D were identified (prevalent CVD: 11; without CVD: 12; unspecified CVD prevalence: 11) and 6 articles [6,24,27,29,46,51] consisting of 7 cohorts were identified for T1D (prevalent CVD: 1; without CVD: 3; unspecified CVD prevalence: 3) (Fig. 1). The total number of individuals were 501,536 for cohorts of T2D with CVD, 27,855,580 for T2D without CVD, 9,046,486 for T2D with unspecified CVD prevalence; 251,538 for T1D with CVD, 18,580,888 for T1D without CVD, and 3,690,911 for T1D unspecified CVD prevalence (Table S3). Of studies investigating T2D, mean age was 57.99, 61.25 and 64.74 in those with CVD, without CVD and unspecified CVD prevalence respectively. Mean baseline recruitment (years) was higher in those with prevalent CVD (2007), compared to without CVD (2004) and unspecified CVD (2001). Most studies were from Europe at 45.45 %, 50.00 % and 54.55 % in those with CVD, without CVD and unspecified CVD prevalence. In T2D, most studies had low risk of bias, with 90.91 %, 91.67 % and 72.73 % reported in populations with CVD, without CVD, and unspecified CVD prevalence. Table S3 summarises the characteristics of all included studies.

Abstract

Background
Anxiety disorder, depression, and bipolar disorder are common psychiatric disorders, and their association with autoimmune thyroiditis (AIT) has been of great interest. This study aimed to investigate the potential causal relationship between these psychiatric disorders and AIT.

Methods
We used publicly available summary statistics from large-scale genome-wide association studies to select, quality control and cluster genetic variant loci associated with anxiety disorder, depression, bipolar disorder and AIT as instrumental variables (IVs). The Mendelian randomization (MR) study mainly used inverse variance weighting (IVW) combined with MR-egger regression and weighted median estimation (WME) to estimate bidirectional causality between mental disorders and AIT. In addition, we conducted heterogeneity and multivariate tests to verify the validity of IVW.

Results
Two-sample bidirectional MR analysis revealed a positive causal link between depression and AIT. The forward MR analysis of IVW (OR 1.614, 95 % CI 1.104–2.358, P = 0.013) and WME (OR 2.314, 95 % CI 1.315–4.074, P = 0.004) demonstrated thatdepression potentially elevate the risk of AIT development, while, our investigation did not uncover a causal relationship between anxiety disorder, bipolar disorder and AIT. The results of reverse MR analysis showed that there was no significant causal relationship between AIT and anxiety disorder, depression, and bipolar disorder (P > 0.05).

Conclusions
The results of the forward MR analysis suggest a positive association between depression, and AIT risk, while indicating no support for a causal link between anxiety disorder or bipolar disorder and AIT risk based on the current data. Subsequent studies will be essential for elucidating the biological mechanisms and potential confounders underlying these associations.

Introduction

Autoimmune thyroiditis (AIT) stands as the most prevalent autoimmune endocrine disorder (Ruggeri et al., 2018), affecting an estimated 3–5 % of the general population (McLeod and Cooper, 2012). Predominantly afflicting women, its incidence escalates with advancing age (McLeod et al., 2014; Hollowell et al., 2002), soaring up to 20 % among elderly women (Surks et al., 2004). Furthermore, it serves as the primary cause of hypothyroidism. In the initial stages, AIT usually manifests with common hypothyroidism symptoms, such as mood disturbances, anxiety, or depression (van Zuuren et al., 2013), while, AIT can also precipitate hyperthyroidism.

Anxiety disorder, depression, and bipolar disorder are prevalent mental disorders with genetic and clinical overlap, suggesting that they may share common etiologic mechanisms (Tondo et al., 2017; Trede et al., 2005; Anttila et al., 2018). Research indicates a shared pattern of abnormal regional intrinsic brain activity in depression and bipolar disorder, particularly implicating the insula, medial prefrontal cortex, and cerebellum (Gong et al., 2020). The lifetime prevalence of anxiety disorder among individuals with bipolar disorder is estimated to be at least 40 %, even exceeding 50 % (Seon et al., 2021; Kessler et al., 1997; Vieta et al., 2001). Recent evidence suggests that the comorbidity of anxiety disorder with bipolar disorder is as high as that of monophasic depression (Preti et al., 2016).

Conclusion

We conducted the first bidirectional Mendelian randomization study of anxiety disorder, depression, bipolar disorder and autoimmune thyroiditis. Depression increases the risk of AIT, while no causal relationship has been found between anxiety disorders, bipolar disorder and AIT. Psychiatric disorders lead to AIT mainly through the expression of related genes affecting the levels of T and B lymphocytes or through the hypothalamic-pituitary-thyroid axis affecting the feedback regulation mechanism to induce thyroid dysfunction. We look forward to more clinical and experimental research data to validate the relationship between psychiatric disorders and AIT. In the meantime, we need to focus on more updated and larger data sets to explore whether there is a causal relationship between other psychiatric disorders and AIT.

Summary

Background
In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance.
Methods
Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens.
Findings
Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis.
Interpretation
Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance.
Funding
Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.

Introduction

Type 2 diabetes (T2D) is a chronic inflammatory disease that is associated with multiple morbidities, including in particular, a heightened risk of cardio-cerebro-vascular disorders, thrombosis and cancer.1,  2,  3 More than 450 million people are living with diabetes, a number expected to grow to ∼650 million by 2040. A key feature of T2D is resistance of adipose tissue and other organs to insulin, often accompanied by hyperinsulinemia.4

Insulin controls key metabolic activities, including inducing glucose uptake, glycogenesis and lipogenesis, inhibiting lipolysis, stimulating protein synthesis, and enhancing adipogenesis.5,  6,  7 Its effects are mediated via cell surface-expressed tyrosine kinase receptors, triggering signaling cascades leading to a plethora of cellular responses, dysregulation of which are believed to result in the associated morbidities. Thus, for example, the increased risk of cancer in T2D is likely due in part to sustained insulin-induced signaling that promotes pathologic angiogenesis, dysregulated cell differentiation and proliferation, with alterations in cell metabolism.8 Mechanisms that regulate insulin signaling are incompletely understood, as are those that underly insulin resistance.9 It is known however, that with obesity and white adipose tissue (WAT) expansion, extracellular matrix remodeling occurs.10 This is associated with inadequate angiogenesis11 due to microenvironmental hypoxia, the latter which is accompanied by dampened adipogenesis and dysregulated expression and/or activation of the insulin receptor (IR).12,13 Adipocytes become dysfunctional with multiple changes, including mitochondrial disturbances, reduced adiponectin release, upregulation of pro-apoptotic and pro-fibrotic genes, increased release of cytokines and adipokines, infiltration with pro-inflammatory cells and suppression of preadipocyte differentiation.14 The associated disturbances in glucose metabolism and insulin sensitivity may occur early, even before evidence of inflammation.

CD248 is a multi-domain, transmembrane glycoprotein expressed on the surface of pre/adipocytes, perivascular cells and macrophages. From studies with gene targeted mice, we and others showed that CD248 participates in hypoxic regulation and angiogenesis,15,  16,  17,  18 and promotes inflammation, fibrosis, and tumorigenesis. Mice lacking CD248 (KO) are healthy and protected against tumor growth,16,19,20 atherosclerosis,21 arthritis,16 thrombosis,22 liver and renal fibrosis23,  24,  25 and lipid accumulation.26 We also recently reported that mice lacking CD248 either globally or specifically in mature adipocytes, are resistant to high fat diet (HFD)-induced weight gain, and are protected against insulin resistance, glucose intolerance and steatosis.18 Notably, WAT health, insulin sensitivity and glucose tolerance could be restored to normal after onset of HFD-induced diabetes by genetically excising CD248 from the mature adipocyte. The relevance of CD248 in glucometabolic health in humans was confirmed by studies of several independent clinical cohorts, showing that CD248 expression in adipocytes strongly and directly correlates with dysfunctional WAT and insulin resistance.18

Results

We previously showed that global lack of CD248 in mice (KO) confers protection of male mice against 9-weeks of a HFD that induced obesity, insulin resistance, glucose intolerance, steatosis, WAT hypoxia, inflammation and fibrosis.18 For the current studies, we found that even exposure to 2 weeks of the HFD induced differences in glucometabolism between male KO mice and their wild-type (WT) counterparts (Supplemental Figures S1–S4). Thus, the KO mice had significantly lower fasting plasma insulin and insulin growth factor (IGF)-1 levels (Supplemental Figure S1) as compared to sibling control, sex matched HFD-fed WT mice, with significantly better responses in glucose tolerance and insulin tolerance tests (GTT & ITT, respectively) (Supplemental Figure S2). ]Immunohistochemical analyses of epididymal (e)WAT from the HFD-fed KO mice followed by fasting x 5 h, revealed less evidence of fibrosis, less infiltration with F480 inflammatory monocytes, and reduced hypoxia, as compared to fasting HFD-fed wild-type (WT) mice (Supplemental Figures S3 and S4). There was no evidence of steatosis in either group (not shown) following the 2 week HFD. Based on these findings, we used this 2-week HFD model to study the mechanisms by which CD248 regulates glucometabolism and insulin sensitivity.

Abstract

There is a complex correlation between thyroid hormones (THs) and liver function. Hypothyroidism as a failure of the thyroid gland to produce adequate thyroid hormones to fulfill the metabolic requirements of the body, may perturb liver structure and function. Emerging evidence suggests the protective effects of vitamin D against liver damage. Herein, this study aimed to investigate the role of vitamin D in hypothyroidism-associated liver injury. Forty male Wistar rats were classified into 4 groups: control, hypothyroid (Hypo) group received 0.05% PTU, Hypo- Vitamin D groups were given 100 and 500 IU/kg vitamin D orally via gavage for 6 weeks. Serum level of liver function including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured. Malondialdehyde (MDA) level, superoxide dismutase (SOD) enzyme activity, and total thiol content were measured as oxidative stress indicators in the liver tissue. Furthermore, to estimate liver tissue fibrosis, Masson’s trichrome staining was done.

Our findings showed that hypothyroidism-induced liver fibrosis was associated with increased levels of ALT, AST and ALP. Though, vitamin D administration could significantly reduce the ALT, AST and ALP in the serum and suppress the accumulation of collagen fibers. Moreover, the activity of SOD and total thiol content was notably reduced, while the MDA content was significantly increased in the PTU- induced hypothyroid rats compared to the control group. Nonetheless, treatment with vitamin D improved mentioned oxidative stress markers in the Hypo-vitamin D groups. In conclusion, vitamin D due to its potential antioxidant and anti-fibrotic properties could be effective in the decrease of hypothyroidism-associated liver injury.

Introduction

Thyroid hormones (THs) play an essential role in tissue growth and normal functioning throughout the life [1,2]. Also, THs have important roles in the regulation of energy metabolism, mitochondrial activity, and active oxygen metabolism [2]. The liver is the major site of the peripheral metabolism of THs. Liver and the thyroid has been well documented to be closely linked, with THs playing essential roles in beta-oxidation as well as cholesterol and carbohydrate metabolism [3]. Therefore, hypothyroidism is associated with unusual lipid patterns with an increase in low-density lipoprotein (LDL) levels as well as higher total cholesterol levels [4]. On the other hand, hypothyroidism is implicated in the etiology of fibrosis and is accompanied with increased production of mucopolysaccharides, resulting in interstitial fibrosis and extracellular water retention [5,6]. The progress of fibrosis is attributable to an abnormal response determined by the accumulation of extracellular matrix proteins such as collagen and fibronectin [7]. In addition, it has been suggested that hypothyroidism can be associated with oxidative stress [8]. Indeed, hypothyroidism by changing lipid panels and increasing reactive oxygen species (ROS) generation enhances tissue oxidative damage [9]. Animal studies have shown that hypothyroidism is in correlation with an increase in the levels of biochemical markers of oxidative stress and reducing the antioxidant levels in liver tissue [2,10]. Moreover, researchers have indicated that there is a positive connection between tissue oxidative damage and fibrosis [11,12]. In the fibrotic liver, damage to hepatic cells disrupts mitochondrial chain function and increases the production of free radicals as a result of lipid peroxidation, as well as activate Kupffer cells, and hepatic stellate cells (HSCs). Among liver cells, HSCs and Kupffer cells play critical roles in fibrosis. In the fibrotic liver, Kupffer cells via releasing profibrogenic factors such as transforming growth factor beta (TGF-β) trigger HSCs activation. HSCs are the predominant precursor cells of liver myofibroblasts and upon activation, by TGF-β, fibrogenic myofibroblasts up-regulate production and deposition of α-smooth muscle actin and extracellular matrix proteins, the most abundant one being type I collagen. Likewise, experimental studies have shown that hypothyroidism can induce up-regulation of collagen type 1 gene expression, causing subsequent fibrosis [[13], [14], [15], [16]].

Conclusions

Our results suggest that thyroid dysfunction is associated with liver damage characterized by abnormal liver function tests as well as liver fibrosis and redox homeostasis. On the other hand, vitamin D supplementation could ameliorate oxidative injury along with changes in liver structure and function in the hypothyroid animals. Vitamin D, with its unique protective effects, has the potential to be repurposed as a therapeutic agent for hepatic diseases associated with fibrosis. Nevertheless, more research still needs to be focused on the regulatory role of vitamin D in inhibiting liver fibro-genesis and to assess the safety and efficiency of this supplementation as a widely available and relatively inexpensive treatment for liver fibrotic conditions.

Summary

Background
Some epidemiological studies have suggested an increase in incidence of type 1 diabetes during the COVID-19 pandemic, however the mechanism(s) behind such an increase have yet to be identified. In this study we aimed to evaluate the possible role of the SARS-CoV-2 virus in the reported increase in the rate of type 1 diabetes.
Methods
In this observational cohort study using data from the Finnish Pediatric Diabetes Register (FPDR), we assessed the incidence of type 1 diabetes (number of children with newly diagnosed type 1 diabetes per 100 000 person-years during the pandemic and the reference period) during the first 18 months of the COVID-19 pandemic in children in Finland younger than 15 years old compared with a reference period which included three corresponding pre-pandemic periods also obtained from the FPDR. Children with confirmed monogenic diabetes were excluded. We also compared the phenotype and HLA genotype of the disease between these two cohorts, and analysed the proportion of newly diagnosed people with type 1 diabetes testing positive for SARS-CoV-2 antibodies.
Findings
785 children and adolescents in Finland were diagnosed with type 1 diabetes from March 1, 2020, to Aug 31, 2021. In the reference period, which comprised three similar 18-month terms (from March 1, 2014, to Aug 31, 2015; March 1, 2016, to Aug 31, 2017; and March 1, 2018, to Aug 31, 2019) 2096 children and adolescents were diagnosed. The incidence of type 1 diabetes was 61·0 per 100 000 person-years (95% CI 56·8–65·4) among children younger than 15 years old during the pandemic, which was significantly higher than during the reference period (52·3 per 100 000 person-years; 50·1–54·6). The incidence rate ratio adjusted for age and sex for the COVID-19 pandemic was 1·16 (1·06–1·25; p=0·0006) when compared with the reference period. The children diagnosed during the COVID-19 pandemic had more often diabetic ketoacidosis (p<0·001), had a higher HbA1c (p<0·001), and tested more frequently positive for glutamic acid debarboxylase antibodies at diagnosis (p<0·001) than those diagnosed before the pandemic. There were no significant differences in the distribution of HLA genotypes between the two periods. Only five of those diagnosed during the pandemic (0·9%) of 583 tested positive for infection-induced SARS-CoV-2 antibodies.
Interpretation
Children and adolescents diagnosed with type 1 diabetes during the pandemic had a more severe disease at diagnosis. The observed increase in type 1 diabetes incidence during the first 18 months could be a consequence of lockdown and physical distancing rather than a direct effect of SARS-CoV-2 infection.
Funding
Helsinki University Hospital Research Funds, EU Horizon 2020 (Versatile emerging infectious disease observatory project), Academy of Finland, Sigrid Jusélius Foundation, Jane & Aatos Erkko Foundation, and Medicinska understödsföreningen Liv och Hälsa.

Introduction

A series of epidemiological studies have reported that the number of people with newly diagnosed type 1 diabetes has increased during the COVID-19 pandemic.1,  2 According to one meta-analysis, the global incidence of type 1 diabetes among children increased by 9·5% from 2019 to 2020.3 However, these findings have been questioned due to methodological weaknesses.4 An increase in diabetic ketoacidosis at diagnosis has also been observed during the pandemic.5,  6,  7 The reasons behind these findings are unknown. There is an ongoing discussion as to whether these observations are a direct effect of a SARS-CoV-2 infection or a consequence of the lockdown and social isolation due to the pandemic.

A direct effect has been implied, either through an injury to the pancreatic β cells by the SARS-CoV-2 virus or through virus-induced precipitation or acceleration of the disease process leading to type 1 diabetes.8 An increase in diabetic ketoacidosis at diagnosis suggests a possible delayed presentation to health-care services, whereas the indirect effect on the incidence of type 1 diabetes might be mediated through an earlier unmasking of the disease process because of the substantially reduced infection load and decreased physical activity, particularly in children. A decreased infection load might affect the immune system, favouring the development of type 1 diabetes, whereas reduced physical activity increases β-cell stress.9 In April 2020, all schools were closed in Finland and parents with children attending day-care centres were asked to keep their children at home, if possible. The biodiversity hypothesis assumes that reduced microbial exposure in early life increases the risk of immune-mediated diseases.10

Results

785 children diagnosed with type 1 diabetes were enrolled during the pandemic period, comprising of 18 months from March 1, 2020, to Aug 31, 2021 (appendix 3 p 5). The reference periods comprised three similar 18-month terms (from March 1, 2014, to Aug 31, 2015; March 1, 2016, to Aug 31, 2017; and March 1, 2018, to Aug 31, 2019). Altogether, 2096 children diagnosed with type 1 diabetes during the combined 54-month reference period joined the FPDR. The baseline characteristics of the participants in the pandemic and reference cohorts are shown in table 1.

Abstract

     Osteoporosis is underrecognized and undertreated in men, even though up to 25% of fractures in patients over the age of 50 years occur in men. Men develop osteoporosis with normal aging and accumulation of comorbidities that cause bone loss. Secondary causes of bone loss may be found in up to 60% of men with osteoporosis. Mortality in men who experience major fragility fracture is greater than in women. Diagnosis of osteoporosis in men is similar to women, based on low-trauma or fragility fractures, and/or bone mineral density dual-energy X-ray absorptiometry (DXA) T-scores at or below −2.5. Because most clinical trials with osteoporosis drugs in men were based on bone density endpoints, not fracture reduction, the antifracture efficacy of approved treatments in men is not as well documented as that in women. Men at a high risk of fracture should be offered treatment to reduce future fractures.

Introduction

     Osteoporosis is a worldwide disease that causes more than nine million fragility fractures annually, one every 3 s [1].

     Men have a lower risk of osteoporosis and fragility fractures than women. This is because women have bones with smaller diameters, lower peak bone mass, a menopause-related bone resorption process, and a higher risk of falls than men [2]. Despite osteoporosis and fragility fractures being less common in men than women, 39% of osteoporotic fractures worldwide occur in men [1]. Data from 2005 indicate that of the 2 million osteoporotic fractures that occur annually in the US, 29% occur in men. This percentage corresponds to an associated cost of 17 billion US dollars [3]. In men and women, the incidence of hip fractures increases exponentially with age, although in men, the increase begins approximately 10 years later [4]. Data from the U.S. 2008 Nationwide Emergency Department Sample showed the incidence of hip fracture in men ranging from 0.56 per 1000 per year at the age of 60 years to 13 per 1000 per year at age 85 years [5]. Similar results were reported in a Norwegian study covering the years 2004–2005, with an incidence of 0.49 per 1000 person-years of hip fractures in men at age 60 and 12.3 per 1000 person-years at age 85 [6]. A 60-year-old man has an approximately 25% risk of having an osteoporotic fracture during his remaining lifetime [7]. Men are less likely than women to be evaluated and receive antiresorptive treatment after a hip fracture [8,9]. The mortality rate associated with hip fractures [10,11] and vertebral and other fractures [12] is higher in men than in women. In a prospective study in community dwelling women and men aged 60 years and older in Australia, mortality after a low trauma fracture was 48% in women and 57% in men within 10 years [13]. The reason for this difference in mortality is not clear, but higher risk of infection in men than in women after a low trauma fracture could be one explanation [14].

Conclusion

     Male osteoporosis occurs less frequently than osteoporosis in postmenopausal women but is still responsible for a substantial disease burden in the population. Approximately 25% of fractures in patients over 50 years occur in men. Osteoporosis in men increases with age as in women, and mortality after major fragility fractures is greater in men than women. Male osteoporosis is defined by the occurrence of fragility fractures, in some parts of the world, only hip and spine fractures or by DXA BMD T-scores of −2.5 or lower at the hip, lumbar spine, and/or forearm. Men having T-scores of −2.5 or lower and prior fragility fractures are at high risk of future fractures. Men with T-scores between −1.0 and −2.5 should be assessed by FRAX or similar tools to determine fracture risk. At least half of men with osteoporosis have secondary causes of bone loss, and identification and treatment of these causes may help prevent further bone loss and possibly improve bone density. Treatment trials of osteoporosis in men have led to the approval of multiple medications for use in men, although these trials were typically small, short in duration, and used bone density rather than fracture endpoints.

 Keywords

Methods

Results

Discussion

Supplementary Data

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Article Info

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Related Articles

Objective
To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology.

Study design
We identified 148 under 10 years of age admitted to King’s College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made.

Results
Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison with those who did not: median age at presentation of 3 months and 30 months and survival rate 75% and 97%, respectively.

Conclusions
NGS was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.

Historically, reports from Europe and North America of children with acute liver failure (ALF) identified infectious, metabolic, and drug-related etiologies but the cause remained unexplained in approximately one-half of all cases.1,  2,  3 Despite the progress made over the last 40 years the rate of indeterminate cases remains ~30%.4 Therefore, challenges remain when evaluating the indeterminate cohort who have a lower chance of spontaneous survival, and higher rates of liver transplantation and death when compared with other diagnostic categories.4,5

The rapid increase in the use of next generation sequencing (NGS) since its advent in 2004 has transformed the way children with rare diseases such as ALF are evaluated. This is particularly relevant when considering the more recently identified monogenic disorders such as those caused by variants in NBAS,6 SCYL1,7 and RINT1.8 Therefore, the purpose of this study was to use NGS technology to identify undiagnosed, monogenic diseases in children who received a diagnosis of indeterminate ALF and to gain insight into how this information may assist us in making therapeutic decisions for affected children in the future.

Context The assessment of “soft” endpoints such as health-related quality of life (HRQOL) is increasingly relevant when evaluating the optimal treatment sequence of novel therapeutic options in patients with advanced prostate cancer (PCa). Objective To systematically review contemporary data regarding HRQOL outcomes in patients with advanced PCa. Evidence acquisition A systematic review of the literature published between January 2011 and March 2019 was performed using the PubMed/Medline Database. In total, 873 articles were screened, and 14 articles including 12 661 patients were selected for synthesis and included in the current analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and European Association of Urology recommendations. Evidence synthesis Regarding HRQOL assessment, the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire was used in 11 of 14 studies, the European Quality of Life 5-Dimensions (EQ-5D) questionnaire in six of 14 studies, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) in two of 14, and its prostate-specific amendment QLQ-PR25 was used in one of 14 studies. Three studies included patients with metastatic castration-sensitive prostate PCa, and found beneficial HRQOL effects for abiraterone acetate and docetaxel compared with standard androgen deprivation therapy. Two studies included patients with nonmetastatic castration-resistant PCa, and positive HRQOL effects for enzalutamide and apalutamide were observed. Nine studies focused on patients with metastatic castration-resistant PCa. Hereby, beneficial HRQOL outcomes were described for enzalutamide, abiraterone acetate, and radium-223. Evidence synthesis was mostly based on studies with a low risk of bias based on standardized risk of bias assessment. Limitations include hampered comparability between different validated questionnaires, lack of baseline values, and unclear impact of supportive care on HRQOL outcomes. Conclusions There is strong evidence from several phase III trials supporting a beneficial effect of current systemic treatment options on HRQOL outcomes in patients with advanced PCa compared with standard androgen deprivation therapy. Patient summary In this systematic review, we provide an overview of contemporary data from large clinical trials on the effect of current treatment strategies on patients’ health-related quality of life (HRQOL). We summarize the assessment tools that have been used to measure HRQOL and show that there are robust data for positive HRQOL effects of numerous agents in different clinical stages of advanced prostate cancer.

1. Introduction

2. Methods

3. Results

4. Discussion

Acknowledgements

References

Abstract

Aims: To investigate levels and changes in diabetes distress over the course of the PRIORITY (Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In people with TYpe 2 diabetes and normoalbuminuria) randomised controlled trial of screening for diabetic kidney disease (DKD) risk among people with type 2 diabetes (T2D) at a specialist diabetes clinic in Denmark.

Methods: Of 436 trial participants with T2D, 216 were invited to complete the 17-item diabetes distress scale at the time of screening (T1, n = 180), immediately after receiving the screening results at 6–8 weeks (T2, n = 169), and at 12 months follow up (T3, n = 107). Linear mixed models were used to explore changes in diabetes distress.

Results: No significant changes in diabetes distress were observed between the time of screening, receiving results, and at 12 months. Changes in diabetes distress were not influenced by diabetes empowerment, sense of coherence, or perceived support for diabetes self-management.

Conclusions: In contrast to previous studies demonstrating that screening programmes can have negative psychological consequences, our findings indicate that participating in this screening programme for DKD does not influence emotional burden or physician-related distress among people with T2D

Introduction

People with diabetes have increased mortality and morbidity. Diabetes-related complications include macrovascular complications such as cardiovascular disease and microvascular complications such as nephropathy, neuropathy, and retinopathy, which are associated with lower quality of life and high healthcare costs.1 Identification and appropriate treatment of people with type 2 diabetes mellitus (T2D) at high risk of developing diabetes-related complications are core disease management activities.

Identification of people at risk of diabetic kidney disease (DKD) typically occurs through screening for albuminuria and kidney function at routine visits when people are still without symptoms of DKD.3 However, the urinary proteomics classifier CKD273 has been suggested as an improved marker for early identification of people at high risk of DKD compared to traditional methods.4 The clinical multicentre intervention trial PRIORITY (Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In people with TYpe 2 diabetes and normoalbuminuria) used this method to screen for future risk of DKD in people with T2D and normal kidney function.

Ramadan is the fasting month in Islam. Muslims around the world observe Ramadan every year, including people with diabetes. Data on the association of fasting in people with diabetes are sparse. The purpose of this study is to assess the association of fasting on cardiovascular risk factors and events in people with diabetes. A comprehensive search was conducted in the following database: Embase, Medline, Cochrane library and CINAHL. The following key terms were used: Ramadan, Ramazan, Ramadhan, Muslim, Islam and fasting. Studies were eligible if they included people with Type 2 diabetes who fasted during Ramadan and reporting results on cardiovascular risk factors or events. Overall 22 studies met inclusion criteria for the review; five studies reported cardiovascular outcomes and 17 reported changes in risk factors. There is insufficient evidence to link Ramadan fasting with increased or reduced incidence of cardiovascular events in people with diabetes, though there were some indication stroke risk may be increased. Findings were inconsistent in term of risk factors as some favoured Ramadan and others did not.

Introduction

Ramadan occurs in the ninth month of the Islamic calendar. During this month, Muslims around the world abstain from food and drinks, including medications, from sunrise to sunset. Because Ramadan follows the lunar calendar, the length of fasting varies depending on the season [1]. Fasting is obligatory for all adults who are capable, but individuals who may be placed at risk by fasting, such as certain high risk patients with diabetes mellitus, are exempt from fasting [2]. However, as Ramadan fasting is one of the five pillars of Islam, many Muslims insist on fasting in some cases against medical advice [3]. There are about 148 million Muslims globally with diabetes [4]. Most of the available guidelines for people with diabetes planning to fast on Ramadan are based on expert opinions. However, there is a lack of scientific evidence on the safety of fasting in people with diabetes [4,5]. During Ramadan, there is a sudden change in daily routines, including eating and sleeping patterns as well as physical activity levels. Muslims who are fasting consume two meals a day, the first before sunrise (suhur) and the second, which is the main meal, after sunset (iftar). These changes in meal time can be associated with changes in sleeping patterns, such as reduced sleep duration, delayed sleep time and increased sleeping and reduced physical activity levels during the day [6–8]. Additionally, these changes can result in changes in insulin resistance as well as multiple neurohormonal changes, including the activation of the hypothalamic-pituitary axis and increased catecholamines, which can lead to endothelial dysfunction and increased cardiovascular events [4,9,10]. Furthermore activation of the HPA axis leads to the secretion of cortisol which results in insulin resistance, increased hepatic glucose output and increased gluconeogenesis [11].

1- Introduction

2- Conclusion

References

Abstract

Alzheimer’s disease (AD) is becoming a threat to aging population all over the world. The pathogenic process of AD is likely initiated many years before clinical onset, thus biomarkers for AD diagnosis are critical for the prevention and therapy for the disease at the early stage in order to reduce the global burden brought by the disease. Saliva is treated as a potential alternative and universal diagnostic fluid that can be collected noninvasively by participants with moderate training and without side effects. Several potential salivary biomarkers, which might prove to be significant diagnostic tools in AD, have been researched. We address here the present and the future of these salivary biological biomarkers for AD.

Introduction

Alzheimer’s disease (AD) is the most common of the neurodegenerative diseases among the aging population, characterized by progressive memory impairment, significant cognitive deficits and irreversible changes in personality and behavior. Although the specific molecular and cellular mechanisms responsible for the etiology and pathogenesis of AD have not been defined, research has revealed that the main pathological characteristics of AD are amyloid-β (Aβ) aggregation and the hyperphosphorylation of tau protein, which eventually develop into senile plaque and neurofibrillary tangles. Together with associated processes, such as inflammation and oxidative stress, these pathological cascades contribute to progressive neurodegeneration (Blennow, de Leon, & Zetterberg, 2006). The majority of AD cases are sporadic late onset types, which are believed to result from environmental factors to a great extent. Age is a significant risk factor for AD. Accompanying the increase in longevity, the prevalence of AD is expected to rise dramatically, causing a large economic and caring burden for health and social services, families, and individuals (Kamer et al., 2008). Thus, it is a great challenge to diagnose and monitor disease progression. A definitive diagnosis of AD currently relies on clinical assessment and pathological evidence only available at postmortem.