Shared Pathophysiology Research Articles

Early microbial markers of periodontal and cardiometabolic diseases in ORIGINS

Periodontitis affects up to 50% of individuals worldwide, and 8.5% are diagnosed with diabetes. The high-comorbidity rate of these diseases may suggest, at least in part, a shared etiology and pathophysiology. Changes in oral microbial communities have been documented in the context of severe periodontitis and diabetes, both independently and together. However, much less is known about the early oral microbial markers of these diseases. We used a subset of the ORIGINS project dataset, which collected detailed periodontal and cardiometabolic information from 787 healthy individuals, to identify early microbial markers of periodontitis and its association with markers of cardiometabolic health. Using state-of-the-art compositional data analysis tools, we identified the log-ratio of Treponema to Corynebacterium bacteria to be a novel Microbial Indicator of Periodontitis (MIP), and found that this MIP correlates with poor periodontal health and cardiometabolic markers early in disease pathogenesis in both subgingival plaque and saliva.

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10−8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10−54), TCF7L2 (P = 4.0 × 10−16), CDKAL1 (P = 1.6 × 10−14), CDKN2A-CDKN2B (P = 4.1 × 10−9) and HKDC1 (P = 2.9 × 10−8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

“Elucidation of the Shared Pathophysiology between Diabetes and COVID-19”

Background: COVID-19 is a rapidly spreading communicable disease worldwide. It varies widely in its spectrum of manifestations, from being mild self-limiting disease, to fulminant disease, often leading to complications and death. Diabetes is an important co-morbidity linked to severity of infection by SARSCoV- 2, which predisposes them to severe pneumonia. Poor glycaemic control is associated with worse outcomes. The disease burden of COVID-19 is continuously increasing, and with a high prevalence of diabetes, it is all the more important to understand the vital aspects of COVID-19 infection in diabetic population. Hence, we try to provide close insights into its pathophysiology, clinical characteristics, recommendations on management and prevention and possible avenues for improving disease outcomes. Methods: PubMed database and Google Scholar were searched using the key terms ‘COVID-19’, ‘SARS CoV- 2’, ‘Corona’ and ‘diabetes’. Full texts of the retrieved articles were accessed and referred. Three main mechanisms which influence COVID-19 disease manifestation in diabetics include: (a) Entry of virus via ACE-2 receptors (b) Action through Dipeptidyl-peptidase-4, and (c) Elevation of glucose concentration in airways by elevated blood glucose.ACE-2 is expressed in alveolar epithelial cells, heart, renal-tubular and intestinal epithelia and pancreas. S-Glycoprotein on the surface of SARS-CoV-2 binds to this ACE-2 and undergoes a conformational change. This allows its’ proteolytic digestion by host cell proteases TMPRSS2 and Furin, leading to internalization of virus. Viral entry into cells triggers an inflammatory response by T-helper-cells and at times, a ‘cytokine storm’, resulting in organ damage. Apart from diminishing neutrophil chemotaxis and reducing phagocytosis, by which diabetes predisposes individuals to infections, there are several specific factors with respect to SARS-CoV2: (i) Increased ACE-2 expression (ii) Raised Furin (iii) Diminished T-cell functioning, and (iv) Increased IL-6 levels. Movement restrictions, increased stress due to social isolation and lack of physical activity further complicates the issue. It is therefore, much essential to raise awareness among front-line workers. Finally, the current situation emphasizes the need for more clinical investigation and define best practices for optimum outcomes. Bangladesh Journal of Medical Science Vol. 21(1) 2022 Page : 19-23

Non-alcoholic fatty liver disease in irritable bowel syndrome: More than a coincidence?

Irritable bowel syndrome (IBS) and non-alcoholic fatty liver disease (NAFLD) are amongst the most common gastrointestinal and liver conditions encountered in primary and secondary care. Recently, there has been interest in the apparent co-incidence of NAFLD in patients with IBS mainly driven by improved understanding of their shared risk factors and pathophysiology. In this paper we summarize the shared risk factors which include; overlapping nutritional and dietary factors as well as shared putative mechanisms of pathophysiology. These include changes in the gut microbiome, gut permeability, immunity, small bowel bacterial overgrowth and bile acid metabolism. This paper describes how these shared risk factors and etiological factors may have practical clinical implications for these highly prevalent conditions. It also highlights some of the limitations of current epidemiological data relating to estimates of the overlapping prevalence of the two conditions which have resulted in inconsistent results and, therefore the need for further research. Early recognition and management of the overlap could potentially have impacts on treatment outcomes, compliance and morbidity of both conditions. Patients with known IBS who have abnormal liver function tests or significant risk factors for NAFLD should be investigated appropriately for this possibility. Similarly, IBS should be considered in patients with NAFLD and symptoms of abdominal pain associated with defecation, an altered bowel habit and bloating.

Diabetic ketoacidosis (DKA) in type 1 diabetes mellitus (T1DM) temporally related to COVID-19 vaccination

SARS-CoV-2 pandemic has claimed millions of lives since its first identification in December 2019. Patients with diabetes are at a high risk of adverse outcomes after COVID-19 infection, whereas infection itself can be associated with severe hyperglycemia, including hyperglycemic emergencies. While the accelerated vaccine development and rollout have considerably decreased morbidity and mortality with reasonable safety, there are emerging reports of worsening of hyperglycemia in response to vaccination, with possible shared pathophysiology with COVID-19 infection-related hyperglycemia. We hereby report two young patients with type 1 diabetes (T1DM) who presented with severe diabetic ketoacidosis (DKA) after receiving second doses of COVISHIELD (ChAdOx1 nCoV-19) and COVAXIN (BBV152- inactivated whole virion) vaccines. Though a causal link cannot be established, post-vaccination immune response can potentially explain this transient worsening of hyperglycemia and hyperglycemic emergencies. We, hence report diabetic ketoacidosis (DKA) following COVID-19 vaccination in T1DM. We suggest that people with diabetes, particularly patients with T1DM with inadequate glycemic control should ideally be closely monitored for hyperglycemia and ketonemia for at least 2 weeks after receiving vaccination for COVID 19.

Developmental Stressors Induce Innate Immune Memory in Microglia and Contribute to Disease Risk.

Many types of stressors have an impact on brain development, function, and disease susceptibility including immune stressors, psychosocial stressors, and exposure to drugs of abuse. We propose that these diverse developmental stressors may utilize a common mechanism that underlies impaired cognitive function and neurodevelopmental disorders such as schizophrenia, autism, and mood disorders that can develop in later life as a result of developmental stressors. While these stressors are directed at critical developmental windows, their impacts are long-lasting. Immune activation is a shared pathophysiology across several different developmental stressors and may thus be a targetable treatment to mitigate the later behavioral deficits. In this review, we explore different types of prenatal and perinatal stressors and their contribution to disease risk and underlying molecular mechanisms. We highlight the impact of developmental stressors on microglia biology because of their early infiltration into the brain, their critical role in brain development and function, and their long-lived status in the brain throughout life. Furthermore, we introduce innate immune memory as a potential underlying mechanism for developmental stressors’ impact on disease. Finally, we highlight the molecular and epigenetic reprogramming that is known to underlie innate immune memory and explain how similar molecular mechanisms may be at work for cells to retain a long-term perturbation after exposure to developmental stressors.

Event related delta and theta oscillations are reduced in severe obstructive sleep apnea as a possible electrophysiologial evidence of subtle cognitive changes

AbstractBackgroundObstructive Sleep Apnea Syndrome (OSAS) is a common sleep disorder that leads to widespread cognitive impairment when left untreated. OSAS is also reported as a risk factor for developing Alzheimer’s disease. Recent studies report a shared pathophysiology between OSAS and Alzheimer’s disease (Polsek et al., 2018; Baril et al., 2018). Working memory and attention related ERP P300 deficits were previously reported (for a review see, Raggi and Ferri, 2012). This study aims to investigate electrophysiological changes by using time‐frequency analysis to gain a better understanding on cognitive impairment in OSAS.Method56 severe OSAS patients and age, education and gender matched 33 healthy controls were participated to the study. Participants completed a classical auditory oddball task. A complex Morlet with Gabor normalization was applied and total power within four frequency bandwidths, delta (0.5‐3.5 Hz), theta (4‐7 Hz), alpha (8‐13 Hz), and beta (15‐30 Hz), was calculated using Event‐Related Spectral Perturbation (ERSP) analyses.ResultOSAS patients had reduced delta and theta ERPS to target stimuli compared to healthy controls in repeated measures ANOVA yielding a significant main GROUP effect (respectively, [F(1,87)=9.181, p=0.003] and [F(1,87)=5.083, p=0.027]). No differences were found on alpha and beta power.ConclusionWe found reduced delta and theta activity in severe OSAS patients. Delta EROs activity is associated with attention and decision making (Başar ve Stampfer, 1985; Stampfer ve Başar, 1985), whereas theta activity was associated with task induced activation of working memory (Yordanova et al. 2000). Reduced delta and theta EROs activity can be useful indices of subtle cognitive impairment in severe OSAS even before neuropsychological test. These results strengthen our understanding of the cognitive changes in OSAS by means of electrophysiological methodologies. This study was supported by Dokuz Eylul University Scientific Research Projects (Project Number: 2014.KB.SAG.058).

Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

IntroductionSickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices.MethodsWe investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided.ResultsThe median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078).DiscussionIn conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. [Display omitted] DisclosuresGordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Hepatic encephalopathy and depression in chronic liver disease: is the common link systemic inflammation?

Hepatic encephalopathy and depression share a number of clinical features, such as cognitive impairment and psychomotor retardation, and are highly prevalent in patients with chronic liver disease. Both conditions signify a poor prognosis, carry an increased mortality and are major determinants of reduced health related quality of life. The pathophysiology of hepatic encephalopathy is complex. Whilst cerebral accumulation of ammonia is well-recognised as being central to the development of hepatic encephalopathy, systemic inflammation, which acts in synergy with hyperammonaemia, is emerging as a key driver in its development. The pro-inflammatory state is also widely documented in depression, and peripheral to brain communication occurs resulting in central inflammation, behavioural changes and depressive symptoms. Gut dysbiosis, with a similar reduction in beneficial bacteria, increase in pathogens and decreased bacterial diversity, has been observed in both hepatic encephalopathy and depression, and it may be that the resultant increased bacterial translocation causes their shared inflammatory pathophysiology. Whilst the literature on a positive association between hepatic encephalopathy and depression in cirrhosis remains to be substantiated, there is evolving evidence that treatment with psychobiotics may be of dual benefit, improving cognition and mood in cirrhosis.

Identification of Disease-Related Genes That Are Common between Alzheimer's and Cardiovascular Disease Using Blood Genome-Wide Transcriptome Analysis.

Accumulating evidence has suggested a shared pathophysiology between Alzheimer’s disease (AD) and cardiovascular disease (CVD). Based on genome-wide transcriptomes, specifically those of blood samples, we identify the shared disease-related signatures between AD and CVD. In addition to gene expressions in blood, the following prior knowledge were utilized to identify several candidate disease-related gene (DRG) sets: protein–protein interactions, transcription factors, disease–gene relationship databases, and single nucleotide polymorphisms. We selected the respective DRG sets for AD and CVD that show a high accuracy for disease prediction in bulk and single-cell gene expression datasets. Then, gene regulatory networks (GRNs) were constructed from each of the AD and CVD DRG sets to identify the upstream regulating genes. Using the GRNs, we identified two common upstream genes (GPBP1 and SETDB2) between the AD and CVD GRNs. In summary, this study has identified the potential AD- and CVD-related genes and common hub genes between these sets, which may help to elucidate the shared mechanisms between these two diseases.

Examining unmet needs in the management of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease driven by a type 2 immune response and characterized by the accumulation of immune cells (eosinophils, basophils, and mast cells) in the esophagus. Patients may present with EoE at any age, and its prevalence is similar across age groups in the United States. If EoE is suspected, an endoscopy with biopsy is required to confirm the diagnosis; endoscopy allows clinicians to evaluate for the presence of rings, furrows, exudates, edemas, and/or strictures and biopsy helps to identify the associated histological changes, including eosinophilic infiltration of the esophageal mucosa. Symptoms of EoE vary by age and include dysphagia, impaction, regurgitation, chest and/or abdominal pain, and vomiting. Allergic comorbidities (eg, allergic rhinitis, asthma, or atopic dermatitis) are common among patients with EoE, which suggests that there may be a shared pathophysiology underlying these conditions. The symptoms of EoE vary widely from patient to patient, and delays in diagnosis are common. Disease progression may lead to lasting damage, including scarring and fibrosis of the esophagus, underscoring the need for early diagnosis and treatment to reduce the clinical, economic, and humanistic burden associated with EoE. Current standard of care treatment options include diet therapy, esophageal dilation, proton pump inhibitors, and topical swallowed corticosteroids; however, these treatments may not provide optimal disease management over the long term. The symptoms of EoE, its complications, and disease management considerations (eg, dietary limitations) are associated with diminished quality of life. There remains an unmet need for long-term management options. It is important for stakeholders to understand the current treatment landscape and unmet needs when considering the assessment of future therapies.

Autonomic activity, posttraumatic and nontraumatic nightmares, and PTSD after trauma exposure.

Nightmares are a hallmark symptom of posttraumatic stress disorder (PTSD). This strong association may reflect a shared pathophysiology in the form of altered autonomic activity and increased reactivity. Using an acoustic startle paradigm, we investigated the interrelationships of psychophysiological measures during wakefulness and PTSD diagnosis, posttraumatic nightmares, and nontraumatic nightmares. A community sample of 122 trauma survivors were presented with a series of brief loud tones, while heart rate (HRR), skin conductance (SCR), and orbicularis oculi electromyogram (EMGR) responses were measured. Prior to the tone presentations, resting heart rate variability (HRV) was assessed. Nightmares were measured using nightmare logs. Three dichotomous groupings of participants were compared: (1) current PTSD diagnosis (n = 59), no PTSD diagnosis (n = 63), (2) those with (n = 26) or without (n = 96) frequent posttraumatic nightmares, and (3) those with (n = 22) or without (n = 100) frequent nontraumatic nightmares. PTSD diagnosis was associated with posttraumatic but not with nontraumatic nightmares. Both PTSD and posttraumatic nightmares were associated with a larger mean HRR to loud tones, whereas nontraumatic nightmare frequency was associated with a larger SCR. EMGR and resting HRV were not associated with PTSD diagnosis or nightmares. Our findings suggest a shared pathophysiology between PTSD and posttraumatic nightmares in the form of increased HR reactivity to startling tones, which might reflect reduced parasympathetic tone. This shared pathophysiology could explain why PTSD is more strongly related to posttraumatic than nontraumatic nightmares, which could have important clinical implications.

Abnormal Pulmonary Lymphatic Flow on Novel Lymphangiographic Imaging Supports a Common Etiology of Lymphatic Plastic Bronchitis and Nontraumatic Chylothorax.

Background: This study evaluates whether dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) and thoracic duct lymphangiography (TDL) findings in adults with lymphatic plastic bronchitis (PB) and/or nontraumatic chylothorax (NTC) support a shared pathophysiology. Materials and Results: Retrospective review of clinical and imaging findings in patients who underwent DCMRL and TDL at a single institution from March 2017 to March 2019. Categorical variables were compared with Fisher's exact test. Twenty-eight patients (median age 61 ± 21 years, 15 women) presenting with lymphatic PB (n = 13), NTC (n = 10), or both (n = 5) were included. Lymphatic imaging demonstrated pulmonary lymphatic perfusion (PLP) in all patients. A patent thoracic duct (TD) with retrograde flow was seen in 53.4% (7/13) of patients with PB, 60% (6/10) of patients with NTC, and 20% (1/5) of patients with both (p = 0.69). An occluded TD with retrograde flow was seen in 30.8% (4/13) of patients with PB, 30% (3/10) of patients with NTC, and 80% (4/5) of patients with both (p = 0.12). Similar patterns of PLP between DCMRL and TDL were seen in 96.2% (25/26) of patients. Conclusions: DCMRL and TDL demonstrated similar findings in patients with lymphatic PB and/or NTC, supporting a common etiology. This supports the hypothesis that the clinical presentation depends on the proximity of abnormal lymphatic vessels to the pleural cavity, resulting in chylothorax, or bronchial mucosa, resulting in PB.

Distinct Signatures of Genomic Copy Number Variants Define Subgroups of Merkel Cell Carcinoma Tumors.

Simple SummaryCancer results from genetic changes in cells. These changes are often mutations that alter the DNA sequence of critical genes. However, duplications and deletions in cancer-related genes can also contribute to malignant transformation. In this study we use Nanostring technology to assess DNA copy number changes in samples of Merkel cell carcinoma (MCC), a rare and aggressive neuroendocrine skin tumor. We were able to identify recurrent amplifications and deletions in cancer-related genes. We also found that MCC tumors grouped into three distinct copy number variant profiles. The first group consisted of tumors with multiple deletions. The second group contained tumors with low levels of genomic structural alterations. The last group comprised tumors containing multiple amplifications. Our study suggests that most MCC tumors are associated with deletions in cancer-related genes or are lacking in copy number changes, whereas a small percentage of tumors are associated with genomic amplifications.Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Most MCC tumors contain integrated Merkel cell polyomavirus DNA (virus-positive MCC, VP-MCC) and carry a low somatic mutation burden whereas virus-negative MCC (VN-MCC) possess numerous ultraviolet-signature mutations. In contrast to viral oncogenes and sequence mutations, little is known about genomic structural variants in MCC. To identify copy number variants in commonly altered genes, we analyzed genomic DNA from 31 tumor samples using the Nanostring nCounter copy number cancer panel. Unsupervised clustering revealed three tumor groups with distinct genomic structural variant signatures. The first cluster was characterized by multiple recurrent deletions in genes such as RB1 and WT1. The second cluster contained eight VP-MCC and displayed very few structural variations. The final cluster contained one VP-MCC and four VN-MCC with predominantly genomic amplifications in genes like MDM4, SKP2, and KIT and deletions in TP53. Overall, VN-MCC contained more structure variation than VP-MCC but did not cluster separately from VP-MCC. The observation that most MCC tumors demonstrate a deletion-dominated structural group signature, independent of virus status, suggests a shared pathophysiology among most VP-MCC and VN-MCC tumors.

OUTCOMES FOR PATIENTS WITH ACUTE MYOCARDIAL INFARCTION AND IBD: ULCERATIVE COLITIS VERSUS CROHN’S DISEASE- AN ANALYSIS OF THE NATIONAL INPATIENT SAMPLE 2015–2017

Abstract Introduction There is a scarcity of data on the influence of sex, race, insurance status on mortality, hospital length of stay (LOS), and total hospital charges for patients with ulcerative colitis (UC) and acute myocardial infarction (AMI) versus patients with Crohn’s disease and AMI. Previous studies have identified that patients with inflammatory bowel disease (IBD) have a lower incidence of AMI compared to the general population, but Ulcerative Colitis has not been compared to Crohn’s Disease for AMI. The aim of this study was to identify risk factors in a national population cohort (in the USA) admitted to hospital between 2015 and 2017. Methods All patients aged 18 years with AMI and UC and AMI and Crohn’s disease,who had been admitted to hospital between 2015 and 2017, were identified from the US Nationwide Inpatient Sample (NIS), a large publicly available all-payer inpatient care database in the USA. Multivariate regression analysis was used to estimate the odds ratios of in-hospital mortality, average length of hospital stay, and hospital charges, after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics. Results Our study identified approximately 200,000 patients who had been discharged with either UC or Crohn’s disease from 2015 to 2017. Of these patients, 208 were admitted with UC and AMI versus 258 with Crohn’s disease and AMI. The analysis revealed that mortality was decreased (OR -1.19, p &amp;lt;0.237), length of stay (LOS) was increased (OR 2.08, p &amp;lt;0.038), and total hospital charges were increased (OR 3.54, p &amp;lt;0.0001) for patients with UC and AMI compared to patients with Crohn’s disease and AMI. Independent positive predictors of mortality were age, black race, and Medicaid insurance. Independent positive predictors of increased hospital LOS were age and Hispanic ethnicity. Independent positive predictors of increased total hospital charges were Hispanic ethnicity and Medicare insurance. Conclusions Patients with UC and AMI have increased LOS and total hospital charges compared to patients with Crohn’s disease and AMI. We identified key drivers for these outcomes. Previous studies showed that patients with IBD had a lower incidence of AMI compared to the general population, but newer studies demonstrate that patients with IBD may be at higher risk. This could possibly be related to the underlying shared pathophysiology of inflammation. In the future, more randomized clinical trials are required to compare patients with UC to patients with Crohn’s disease, especially the impact of therapeutic interventions on the incidence of AMI for this patient population.

Comorbidity in chronic kidney disease: a large cross-sectional study of prevalence in Scottish primary care.

BackgroundChronic kidney disease (CKD) is commonly comorbid with hypertension, diabetes, and cardiovascular disease (CVD). However, the extent of comorbidity in CKD across a range of concordant (shared pathophysiology and/or treatment) conditions and discordant (unrelated pathophysiology and/or different or contradictory treatment) conditions is not well documented.AimTo ascertain the prevalence of comorbidity, across 39 physical and mental health comorbidities, in adults with CKD in a large, nationally representative primary care population.Design and settingCross-sectional analysis of a primary care dataset representing 1 274 374 adults in Scotland.MethodThis study was a secondary analysis of general practice electronic medical record data using binary logistic regression models adjusted for age, sex, and socioeconomic status. Data of adults aged ≥25 years and 40 long-term conditions were used.ResultsA total of 98.2% of adults with CKD had at least one comorbidity, versus 51.8% in controls. After adjustment for age, sex, and deprivation, people with CKD were more likely to have 1 (adjusted odds ratio [aOR] 6.5, 95% confidence interval [CI] = 6.0 to 7.1), 2–3 (aOR 15.2, 95% CI = 14.0 to 16.5), 4–6 (odds ratio [OR] 26.6, 95% CI = 24.4 to 28.9), and ≥7 other conditions (OR 41.9, 95% CI = 38.3 to 45.8). Furthermore, all concordant (seven out of seven), the majority of discordant physical health conditions (17 out of 24), and mental health conditions (six out of eight) had statistically significant positive associations with CKD after adjustment.ConclusionChronic kidney disease is associated with extreme comorbidity across a wide range of mental and physical conditions. Routine care for people with CKD should include recognition and management of comorbidities, and clinical guidelines should support clinicians to do this.

Approaching Shared Pathophysiology in Immune-Mediated Diseases through Functional Genomics.

Immune-mediated diseases (IMDs) are complex pathologies that are strongly influenced by environmental and genetic factors. Associations between genetic loci and susceptibility to these diseases have been widely studied, and hundreds of risk variants have emerged during the last two decades, with researchers observing a shared genetic pattern among them. Nevertheless, the pathological mechanism behind these associations remains a challenge that has just started to be understood thanks to functional genomic approaches. Transcriptomics, regulatory elements, chromatin interactome, as well as the experimental characterization of genomic findings, constitute key elements in the emerging understandings of how genetics affects the etiopathogenesis of IMDs. In this review, we will focus on the latest advances in the field of functional genomics, centering our attention on systemic rheumatic IMDs.

Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology.

In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD+), are still unclear. In 80 EOA-patients, we determined the EOAD+-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD+-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD+-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus (p = 0.001)). Genetic network and functional enrichment analysis in EOAD+-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD+-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD+-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.

The Co-occurrence of Pediatric Obesity and ADHD: an Understanding of Shared Pathophysiology and Implications for Collaborative Management.

To describe what is known about the association between obesity and attention-deficit hyperactivity disorder (ADHD) in children along with the co-occurring conditions of sleep dysfunction, loss of control/binge eating disorder (LOC-ED/BED), and anxiety. Obesity and ADHD share common brain pathways (hypothalamic, executive, and reward centers) with pathophysiology in these areas manifesting in partial or complete expression of these diseases. Sleep dysfunction, LOC-ED/BED, and anxiety share similar pathways and are associated with this disease dyad. The association of obesity and ADHD with sleep dysfunction, LOC-ED/BED, and anxiety is discussed. An algorithm outlining decision pathways for patients with obesity and with and without ADHD is presented. Future research exploring the complex pathophysiology of both obesity and ADHD as well as co-occurring conditions is needed to develop clinical guidelines and ultimately assist in providing the best evidence-based care.

Brain activation and connectivity in anorexia nervosa and body dysmorphic disorder when viewing bodies: relationships to clinical symptoms and perception of appearance.

Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are characterized by distorted perception of appearance, yet no studies have directly compared the neurobiology associated with body perception. We compared AN and BDD in brain activation and connectivity in relevant networks when viewing images of others' bodies and tested their relationships with clinical symptoms and subjective appearance evaluations. We acquired fMRI data from 64 unmedicated females (20 weight-restored AN, 23 BDD, 21 controls) during a matching task using unaltered or spatial-frequency filtered photos of others' bodies. Using general linear model and independent components analyses we compared brain activation and connectivity in visual, striatal, and parietal networks and performed univariate and partial least squares multivariate analyses to investigate relationships with clinical symptoms and appearance evaluations. AN and BDD showed partially overlapping patterns of hyperconnectivity in the dorsal visual network and hypoconnectivity in parietal network compared with controls. BDD, but not AN, demonstrated hypoactivity in dorsal visual and parietal networks compared to controls. Further, there were significant activity and connectivity differences between AN and BDD in both networks. In both groups, activity and/or connectivity were associated with symptom severity and appearance ratings of others' bodies. Thus, AN and BDD demonstrate both distinct and partially-overlapping aberrant neural phenotypes involved in body processing and visually encoding global features. Nevertheless, in each disorder, aberrant activity and connectivity show relationships to clinically relevant symptoms and subjective perception. These results have implications for understanding distinct and shared pathophysiology underlying perceptual distortions of appearance and may inform future novel treatment strategies.