Chronic pain is a major medical problem that requires new therapeutic options. Discovered by Victor Mutt in 1982, neuropeptide Y (NPY) is rapidly emerging as a master regulator of pain relief. Genetic knockdown of NPY or pharmacological inhibition of its receptors demonstrates that NPY signaling tonically inhibits indices of chronic inflammatory and neuropathic pain. Primary targets of NPY analgesia include neurons in the dorsal horn of the spinal cord and the parabrachial nucleus of the brain that express the Npy1r (Y1) receptor. NPY signaling is enhanced following injury, and endogenous analgesic synergy between Y1 receptors and mu opioid receptors maintain chronic pain sensitization in a latent state of remission. We propose that disruptions to endogenous NPY analgesia may mediate pathological transitions from acute to chronic pain, which could be treated by CNS administration of Y1 agonists or Npy2r (Y2) agonists or antagonists, depending on the pain state. Chemogenetic manipulations or targeted ablations in rodent models of chronic inflammation or peripheral nerve injury establish that spinal Y1-interneurons are necessary and sufficient to elicit behavioral signs of both the sensory and affective dimensions of pain. Transcriptomic and in situ hybridization studies revealed three primary subpopulations of spinal Y1-interneurons that are conserved in higher order mammals, including non-human primates and humans. Spinally directed (intrathecal) administration of Y1-selective pharmacological agonists inhibit pronociceptive neurons that co-express Y1 and gastrin-releasing peptide to inhibit neuropathic pain. To circumvent highly invasive administration routes, ongoing studies are leveraging the intranasal route for delivery of NPY into the brain.
{"title":"The pharmacotherapeutic potential of neuropeptide Y for chronic pain","authors":"Al A. Nie, Bradley K. Taylor","doi":"10.1111/joim.20118","DOIUrl":"10.1111/joim.20118","url":null,"abstract":"<p>Chronic pain is a major medical problem that requires new therapeutic options. Discovered by Victor Mutt in 1982, neuropeptide Y (NPY) is rapidly emerging as a master regulator of pain relief. Genetic knockdown of NPY or pharmacological inhibition of its receptors demonstrates that NPY signaling tonically inhibits indices of chronic inflammatory and neuropathic pain. Primary targets of NPY analgesia include neurons in the dorsal horn of the spinal cord and the parabrachial nucleus of the brain that express the Npy1r (Y1) receptor. NPY signaling is enhanced following injury, and endogenous analgesic synergy between Y1 receptors and mu opioid receptors maintain chronic pain sensitization in a latent state of remission. We propose that disruptions to endogenous NPY analgesia may mediate pathological transitions from acute to chronic pain, which could be treated by CNS administration of Y1 agonists or Npy2r (Y2) agonists or antagonists, depending on the pain state. Chemogenetic manipulations or targeted ablations in rodent models of chronic inflammation or peripheral nerve injury establish that spinal Y1-interneurons are necessary and sufficient to elicit behavioral signs of both the sensory and affective dimensions of pain. Transcriptomic and in situ hybridization studies revealed three primary subpopulations of spinal Y1-interneurons that are conserved in higher order mammals, including non-human primates and humans. Spinally directed (intrathecal) administration of Y1-selective pharmacological agonists inhibit pronociceptive neurons that co-express Y1 and gastrin-releasing peptide to inhibit neuropathic pain. To circumvent highly invasive administration routes, ongoing studies are leveraging the intranasal route for delivery of NPY into the brain.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 4","pages":"280-296"},"PeriodicalIF":9.2,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Denise Mafra, Isabela Brum, Natália A. Borges, Viviane O. Leal, Denis Fouque
The benefits of a low-protein diet (LPD) in patients with altered kidney function remain controversial. Dietary intake studies are inherently complex and may present numerous biases that must be understood and controlled. Due to these challenges, the scientific evidence in this area remains limited and is subject to dispute. However, there is abundant literature showing that excessive protein intake in these patients is linked to cardiovascular issues, oxidative stress, hyperphosphatemia, bone mineral disease, metabolic acidosis, inflammation, and gut dysbiosis, contributing to kidney damage and other concurrent systemic disorders. An LPD remains a valuable recommendation for non-dialysis chronic kidney disease (CKD) patients if age, nutritional status, and disease complications are carefully considered to ensure optimal outcomes. On the one hand, excessive protein intake may lead to the accumulation of nitrogenous waste products, thereby burdening renal function. On the other hand, overly restrictive protein consumption can lead to muscle mass loss, potentially worsening clinical outcomes and patient prognosis. This narrative review highlights the harmful impact of a high-protein diet on kidney function, particularly for those with preexisting kidney impairment or a predisposition to CKD. It also discusses the importance of an individualized and well-monitored protein intake strategy to balance the benefits of protein restriction with the risks of malnutrition.
{"title":"Low-protein diet for chronic kidney disease: Evidence, controversies, and practical guidelines","authors":"Denise Mafra, Isabela Brum, Natália A. Borges, Viviane O. Leal, Denis Fouque","doi":"10.1111/joim.20117","DOIUrl":"10.1111/joim.20117","url":null,"abstract":"<p>The benefits of a low-protein diet (LPD) in patients with altered kidney function remain controversial. Dietary intake studies are inherently complex and may present numerous biases that must be understood and controlled. Due to these challenges, the scientific evidence in this area remains limited and is subject to dispute. However, there is abundant literature showing that excessive protein intake in these patients is linked to cardiovascular issues, oxidative stress, hyperphosphatemia, bone mineral disease, metabolic acidosis, inflammation, and gut dysbiosis, contributing to kidney damage and other concurrent systemic disorders. An LPD remains a valuable recommendation for non-dialysis chronic kidney disease (CKD) patients if age, nutritional status, and disease complications are carefully considered to ensure optimal outcomes. On the one hand, excessive protein intake may lead to the accumulation of nitrogenous waste products, thereby burdening renal function. On the other hand, overly restrictive protein consumption can lead to muscle mass loss, potentially worsening clinical outcomes and patient prognosis. This narrative review highlights the harmful impact of a high-protein diet on kidney function, particularly for those with preexisting kidney impairment or a predisposition to CKD. It also discusses the importance of an individualized and well-monitored protein intake strategy to balance the benefits of protein restriction with the risks of malnutrition.</p>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 4","pages":"319-335"},"PeriodicalIF":9.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Heinz Drexel, Laura Schnetzer, Andreas Leiherer, Peter Fraunberger, Arthur Mader, Christoph H. Saely, Andreas Festa
{"title":"Remnant cholesterol as a driver for atherosclerosis in patients with type 2 diabetes: Insights from a long-term prospective cohort study","authors":"Heinz Drexel, Laura Schnetzer, Andreas Leiherer, Peter Fraunberger, Arthur Mader, Christoph H. Saely, Andreas Festa","doi":"10.1111/joim.70001","DOIUrl":"https://doi.org/10.1111/joim.70001","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 3","pages":"268-272"},"PeriodicalIF":9.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Dear Editor,</p><p>Antimicrobial resistance (AMR) is the phenomenon that occurs when infections are no longer sensitive to commercially available antimicrobials. Today, it is considered to be among the major global health problems. Among the most important strategies to counter the AMR phenomenon is to find alternative therapeutic strategies to common antimicrobials. Antimicrobial peptides (AMPs) are a class of naturally occurring molecules that act as crucial components of the innate immune system in a wide range of organisms, including humans, animals, plants and microorganisms. These peptides exhibit broad-spectrum antimicrobial properties, enabling them to target and neutralize a variety of pathogens, including bacteria, fungi, viruses and parasites. Recently, AMPs have been increasingly studied as potential therapeutic alternatives to conventional antibiotics. However, there are still many questions to be answered before their established use in clinical practice. The unique structure and different modes of action of AMP make them promising candidates for therapeutic development [<span>1, 2</span>]. The mechanisms of action of AMP are multiple, such as membrane disruption and potential intracellular targeting. Furthermore, through their amphipathic nature and cationic charge, AMPs selectively interact with negatively charged microbial membranes, distinguishing them from host cells. Upon binding, they insert into the lipid bilayer, leading to the formation of pores, thinning of the membrane or its complete disintegration, resulting in ion leakage, loss of membrane potential and eventual cell lysis. In addition to membrane disruption, some AMPs penetrate microbial cells to inhibit vital processes, including DNA/RNA synthesis, protein translation and enzyme activity, such as blocking cell wall biosynthesis. This dual mechanism of membrane attack and intracellular action enhances their broad-spectrum efficacy against bacteria, fungi, viruses and even drug-resistant strains, minimizing the development of resistance. In addition, an immunomodulatory role has been demonstrated for some AMPs, further enhancing host defence. Their versatility makes them promising candidates for the next generation of antimicrobial therapies [<span>3</span>]. Human defensin HBD 2, for instance, is being studied for its potential in the treatment of skin infections, respiratory tract infections and even inflammatory diseases [<span>4</span>]. Cathelicidins are another group of AMPs that demonstrate strong antimicrobial properties. The human cathelicidin, LL-37, is particularly effective against Gram-positive bacteria and has shown potential in the treatment of skin wounds and respiratory infections. LL-37 is also known for its immunomodulatory properties, which help regulate immune responses and promote wound healing. Melittin, derived from bees, is another potent AMP that acts by disrupting bacterial cell membranes. It has shown promise in the treatment of bacteria
{"title":"Therapeutic innovations to counter antimicrobial-resistant infections and antimicrobial peptides","authors":"Antonio Vitiello","doi":"10.1111/joim.70005","DOIUrl":"10.1111/joim.70005","url":null,"abstract":"<p>Dear Editor,</p><p>Antimicrobial resistance (AMR) is the phenomenon that occurs when infections are no longer sensitive to commercially available antimicrobials. Today, it is considered to be among the major global health problems. Among the most important strategies to counter the AMR phenomenon is to find alternative therapeutic strategies to common antimicrobials. Antimicrobial peptides (AMPs) are a class of naturally occurring molecules that act as crucial components of the innate immune system in a wide range of organisms, including humans, animals, plants and microorganisms. These peptides exhibit broad-spectrum antimicrobial properties, enabling them to target and neutralize a variety of pathogens, including bacteria, fungi, viruses and parasites. Recently, AMPs have been increasingly studied as potential therapeutic alternatives to conventional antibiotics. However, there are still many questions to be answered before their established use in clinical practice. The unique structure and different modes of action of AMP make them promising candidates for therapeutic development [<span>1, 2</span>]. The mechanisms of action of AMP are multiple, such as membrane disruption and potential intracellular targeting. Furthermore, through their amphipathic nature and cationic charge, AMPs selectively interact with negatively charged microbial membranes, distinguishing them from host cells. Upon binding, they insert into the lipid bilayer, leading to the formation of pores, thinning of the membrane or its complete disintegration, resulting in ion leakage, loss of membrane potential and eventual cell lysis. In addition to membrane disruption, some AMPs penetrate microbial cells to inhibit vital processes, including DNA/RNA synthesis, protein translation and enzyme activity, such as blocking cell wall biosynthesis. This dual mechanism of membrane attack and intracellular action enhances their broad-spectrum efficacy against bacteria, fungi, viruses and even drug-resistant strains, minimizing the development of resistance. In addition, an immunomodulatory role has been demonstrated for some AMPs, further enhancing host defence. Their versatility makes them promising candidates for the next generation of antimicrobial therapies [<span>3</span>]. Human defensin HBD 2, for instance, is being studied for its potential in the treatment of skin infections, respiratory tract infections and even inflammatory diseases [<span>4</span>]. Cathelicidins are another group of AMPs that demonstrate strong antimicrobial properties. The human cathelicidin, LL-37, is particularly effective against Gram-positive bacteria and has shown potential in the treatment of skin wounds and respiratory infections. LL-37 is also known for its immunomodulatory properties, which help regulate immune responses and promote wound healing. Melittin, derived from bees, is another potent AMP that acts by disrupting bacterial cell membranes. It has shown promise in the treatment of bacteria","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 4","pages":"361-362"},"PeriodicalIF":9.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antonio García-Ríos, Juan Luis Romero-Cabrera, Juan Francisco Alcalá-Díaz, Gracia M. Quintana-Navarro, Laura Martín-Piedra, Antonio Pablo Arenas-de Larriva, Jose David Torres-Peña, Fernando Rodriguez-Cantalejo, Stefanos N. Kales, José M. Ordovás, Pablo Pérez-Martínez, Javier Delgado-Lista, José López-Miranda
Background
Evidence suggests interactions between sleep and diet that could modify coronary heart disease (CHD) risk. This study aims to investigate the association between sleep duration and incidence of major cardiovascular events (MACE) and the impact of dietary interventions (Mediterranean or low-fat diet) from the Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention (CORDIOPREV) study (NCT00924937).
Methods
A total of 952 subjects were stratified into reference (>6 to <8 h per night), short (≤6 h), and long sleep duration pattern (≥8 h) based on self-reported data from the Minnesota Leisure-Time Physical Activity questionnaire over 7 years. The main outcome was the incidence of MACE (myocardial infarction, revascularization procedures, ischemic strokes, peripheral artery disease, and cardiovascular mortality).
Results
MACE occurred in 189 participants: 18.1% in the reference group, 17.7% in the short group, and 29% in the long sleep duration group. Accordingly, the long sleep duration group had a higher risk of MACE compared to the reference and short sleep groups (log-rank p < 0.01, hazard ratio [HR]: 1.59 [95% CI: 1.12–2.26]). Participants assigned to a low-fat diet with long sleep duration had a higher risk of MACE (HR: 1.74 [95% CI: 1.11–2.73]), whereas those assigned to a Mediterranean diet did not show significant differences in risk (HR: 1.35 [95% CI: 0.76–2.41]).
Conclusions
A long sleep duration pattern is associated with a higher risk of MACE among CHD patients. Long-term adherence to a Mediterranean diet may mitigate this association. These findings highlight the importance of considering sleep as a cardiovascular risk factor in clinical practice.
{"title":"Long sleep duration pattern is associated with increased cardiovascular recurrence: Effect of long-term Mediterranean diet from the CORDIOPREV study","authors":"Antonio García-Ríos, Juan Luis Romero-Cabrera, Juan Francisco Alcalá-Díaz, Gracia M. Quintana-Navarro, Laura Martín-Piedra, Antonio Pablo Arenas-de Larriva, Jose David Torres-Peña, Fernando Rodriguez-Cantalejo, Stefanos N. Kales, José M. Ordovás, Pablo Pérez-Martínez, Javier Delgado-Lista, José López-Miranda","doi":"10.1111/joim.20119","DOIUrl":"10.1111/joim.20119","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Evidence suggests interactions between sleep and diet that could modify coronary heart disease (CHD) risk. This study aims to investigate the association between sleep duration and incidence of major cardiovascular events (MACE) and the impact of dietary interventions (Mediterranean or low-fat diet) from the Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention (CORDIOPREV) study (NCT00924937).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 952 subjects were stratified into reference (>6 to <8 h per night), short (≤6 h), and long sleep duration pattern (≥8 h) based on self-reported data from the Minnesota Leisure-Time Physical Activity questionnaire over 7 years. The main outcome was the incidence of MACE (myocardial infarction, revascularization procedures, ischemic strokes, peripheral artery disease, and cardiovascular mortality).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MACE occurred in 189 participants: 18.1% in the reference group, 17.7% in the short group, and 29% in the long sleep duration group. Accordingly, the long sleep duration group had a higher risk of MACE compared to the reference and short sleep groups (log-rank <i>p </i>< 0.01, hazard ratio [HR]: 1.59 [95% CI: 1.12–2.26]). Participants assigned to a low-fat diet with long sleep duration had a higher risk of MACE (HR: 1.74 [95% CI: 1.11–2.73]), whereas those assigned to a Mediterranean diet did not show significant differences in risk (HR: 1.35 [95% CI: 0.76–2.41]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>A long sleep duration pattern is associated with a higher risk of MACE among CHD patients. Long-term adherence to a Mediterranean diet may mitigate this association. These findings highlight the importance of considering sleep as a cardiovascular risk factor in clinical practice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 3","pages":"237-250"},"PeriodicalIF":9.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Páll Guðjónsson, Ari J. Jóhannesson, Elías Eyþórsson, Karl Andersen
Background
Amiodarone induced thyroid dysfunction (AITD) is divided into amiodarone induced thyrotoxicosis (AIT) and amiodarone induced hypothyroidism (AIH). The prevalence of them varies from 1.2% to 12% for AIT and 12%–17% for AIH.
Objectives
To study the incidence and complications of AITD.
Methods
The cohort comprised all euthyroid patients who filled their first amiodarone prescription in Iceland in 2014, 262 persons. Data were gathered with chart review, and diagnosis confirmed with thyroid function tests. The cumulative incidence accounting for death as a competing risk was estimated for AIT, AIH, and AITD with three separate Fine-Gray models.
Results
The overall incidence of AIT, AIH, and AITD was 9.2% (95% CI: 5.6%–12.7%), 13.4% (95% CI: 9.2%–17.5%), and 22.5% (95% CI: 17.4%–27.6%), respectively, and the 5-year cumulative incidence in the same order was 19.0% (95% CI: 11.9%–25.5%), 21.8% (95% CI: 14.7%–28.2%), and 38.5% (95% CI: 30.4%–45.7%). The highest yearly incidence rate of AIT was 9.8% during the third treatment year, and for AIH, it was 9.8% during the first year of treatment. The complications of AIT were hypothyroidism (8%), thyroidectomy (8%), hospitalizations (36%), and death (4%). Most patients (91.7%) with AIH were placed on thyroid replacement therapy.
Discussion
Nearly 40% of patients taking amiodarone for 5 years acquire thyroid dysfunction, which is higher than previously described. Frequent monitoring of thyroid function should be considered during the high-risk periods of the first and third treatment years.
{"title":"Amiodarone induced thyroid dysfunction: A high cumulative incidence in a nationwide cohort study in Iceland","authors":"Páll Guðjónsson, Ari J. Jóhannesson, Elías Eyþórsson, Karl Andersen","doi":"10.1111/joim.20115","DOIUrl":"10.1111/joim.20115","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Amiodarone induced thyroid dysfunction (AITD) is divided into amiodarone induced thyrotoxicosis (AIT) and amiodarone induced hypothyroidism (AIH). The prevalence of them varies from 1.2% to 12% for AIT and 12%–17% for AIH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To study the incidence and complications of AITD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The cohort comprised all euthyroid patients who filled their first amiodarone prescription in Iceland in 2014, 262 persons. Data were gathered with chart review, and diagnosis confirmed with thyroid function tests. The cumulative incidence accounting for death as a competing risk was estimated for AIT, AIH, and AITD with three separate Fine-Gray models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The overall incidence of AIT, AIH, and AITD was 9.2% (95% CI: 5.6%–12.7%), 13.4% (95% CI: 9.2%–17.5%), and 22.5% (95% CI: 17.4%–27.6%), respectively, and the 5-year cumulative incidence in the same order was 19.0% (95% CI: 11.9%–25.5%), 21.8% (95% CI: 14.7%–28.2%), and 38.5% (95% CI: 30.4%–45.7%). The highest yearly incidence rate of AIT was 9.8% during the third treatment year, and for AIH, it was 9.8% during the first year of treatment. The complications of AIT were hypothyroidism (8%), thyroidectomy (8%), hospitalizations (36%), and death (4%). Most patients (91.7%) with AIH were placed on thyroid replacement therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>Nearly 40% of patients taking amiodarone for 5 years acquire thyroid dysfunction, which is higher than previously described. Frequent monitoring of thyroid function should be considered during the high-risk periods of the first and third treatment years.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 3","pages":"228-236"},"PeriodicalIF":9.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marcel Ballin, Örjan Ekblom, Anna Nordström, Viktor H. Ahlqvist, Peter Nordström
Objective
Examine the association between adolescent cardiorespiratory fitness and future risk of depression and dispensation of antidepressants, including the role of familial confounding.
Methods
A cohort study with sibling-comparisons based on Swedish men who participated in mandatory military conscription examinations from 1972 to 1995. The exposure was cardiorespiratory fitness estimated using a maximal ergometer bicycle test. The outcomes were depression diagnosis in specialized outpatient or inpatient care and dispensation of antidepressants until 31 December 2023.
Results
A total of 1,013,885 men (mean age 18.3 years), of which 410,198 were full siblings, were followed until a median age of 56.8 years, during which 47,283 were diagnosed with depression and 237,409 were dispensed antidepressants. In cohort analysis, the highest decile of fitness had lower risks of depression (adjusted hazard ratio [HR] 0.54, [95% confidence interval, 0.52, 0.57]) and antidepressants (HR 0.63; 0.62, 0.65) compared to the lowest decile, with differences in the standardized cumulative incidence by age 65 of −3.9% and −12.3%, respectively. In sibling-comparison analyses accounting for unobserved familial confounders, the associations attenuated for both depression (HR 0.67, 0.59–0.75; incidence difference −2.4%) and antidepressants (HR 0.76, 0.72–0.80; incidence difference −7.2%). Hypothetically shifting everyone to the highest decile of fitness was associated with a preventable fraction of 29.1% for depression and 17.8% for antidepressants in cohort analysis, which attenuated to 17.6% and 10.4% in sibling-comparisons.
Conclusions
High levels of adolescent cardiorespiratory fitness are associated with lower risks of future depression and antidepressants, but the associations might be overstated due to familial confounding.
{"title":"Overstated association between adolescent physical fitness and adulthood depression risk due to familial factors","authors":"Marcel Ballin, Örjan Ekblom, Anna Nordström, Viktor H. Ahlqvist, Peter Nordström","doi":"10.1111/joim.20109","DOIUrl":"10.1111/joim.20109","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Examine the association between adolescent cardiorespiratory fitness and future risk of depression and dispensation of antidepressants, including the role of familial confounding.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A cohort study with sibling-comparisons based on Swedish men who participated in mandatory military conscription examinations from 1972 to 1995. The exposure was cardiorespiratory fitness estimated using a maximal ergometer bicycle test. The outcomes were depression diagnosis in specialized outpatient or inpatient care and dispensation of antidepressants until 31 December 2023.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 1,013,885 men (mean age 18.3 years), of which 410,198 were full siblings, were followed until a median age of 56.8 years, during which 47,283 were diagnosed with depression and 237,409 were dispensed antidepressants. In cohort analysis, the highest decile of fitness had lower risks of depression (adjusted hazard ratio [HR] 0.54, [95% confidence interval, 0.52, 0.57]) and antidepressants (HR 0.63; 0.62, 0.65) compared to the lowest decile, with differences in the standardized cumulative incidence by age 65 of −3.9% and −12.3%, respectively. In sibling-comparison analyses accounting for unobserved familial confounders, the associations attenuated for both depression (HR 0.67, 0.59–0.75; incidence difference −2.4%) and antidepressants (HR 0.76, 0.72–0.80; incidence difference −7.2%). Hypothetically shifting everyone to the highest decile of fitness was associated with a preventable fraction of 29.1% for depression and 17.8% for antidepressants in cohort analysis, which attenuated to 17.6% and 10.4% in sibling-comparisons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>High levels of adolescent cardiorespiratory fitness are associated with lower risks of future depression and antidepressants, but the associations might be overstated due to familial confounding.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 3","pages":"200-213"},"PeriodicalIF":9.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hashmat Sayed Zohori Bahrami, Peter Godsk Jørgensen, Jens Dahlgaard Hove, Ulrik Dixen, Line Jee Hartmann Rasmussen, Jesper Eugen-Olsen, Peter Rossing, Magnus T. Jensen
Background
Type 1 diabetes (T1D) increases premature mortality risk, with cardiovascular disease being the leading cause. Chronic inflammation may play a role. Associations between inflammatory biomarkers and mortality are not well-known in T1D.
Methods
We evaluated a prospective clinical cohort with T1D without known cardiovascular disease. The inflammatory biomarkers soluble-urokinase-plasminogen-activator-receptor (suPAR) and interleukin-6 (IL-6) were measured. Patients were stratified by elevated/low suPAR or IL-6, or simultaneously elevated suPAR and IL-6. Primary and secondary endpoints were all-cause mortality and major adverse cardiovascular events (MACE), respectively. Cox models were adjusted for 10 Steno T1 Risk Engine variables and inflammatory biomarkers. Net reclassification improvement (NRI) and C-statistics were calculated.
Results
Among 962 participants (52% male, median age 50, median follow-up 13.1 years), mortality was higher in patients with elevated inflammation: 31% for elevated versus 9% for low suPAR; 30% for elevated versus 11% for low IL-6; and 50% for simultaneously elevated suPAR and IL-6 versus 5% for low suPAR and IL-6. In fully adjusted models, elevated inflammation was associated with mortality (hazard ratios [95% confidence intervals]: suPAR 2.0 [1.4–3.0, p < 0.001], IL-6 1.8 [1.3–2.6; p = 0.001], and combined 4.0 [2.3–7.2, p < 0.001]) and MACE (suPAR 1.9 [1.4–2.6, p < 0.001], IL-6 1.4 [1.0–1.8, p = 0.034], and combined 2.6 [1.7–4.1, p < 0.001]). Adding suPAR, IL-6, and their combination to the Steno T1 Risk Engine improved NRI for mortality by 61%, 53%, and 84%, respectively, whereas C-statistics improved from 0.808 to 0.829, 0.826, and 0.881, respectively.
Conclusions
suPAR, IL-6, and especially their combination independently predicts all-cause mortality and MACE in T1D without known cardiovascular disease.
{"title":"Soluble urokinase plasminogen activator receptor and interleukin-6 improves prediction of all-cause mortality and major adverse cardiovascular events in Type 1 diabetes","authors":"Hashmat Sayed Zohori Bahrami, Peter Godsk Jørgensen, Jens Dahlgaard Hove, Ulrik Dixen, Line Jee Hartmann Rasmussen, Jesper Eugen-Olsen, Peter Rossing, Magnus T. Jensen","doi":"10.1111/joim.20108","DOIUrl":"10.1111/joim.20108","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Type 1 diabetes (T1D) increases premature mortality risk, with cardiovascular disease being the leading cause. Chronic inflammation may play a role. Associations between inflammatory biomarkers and mortality are not well-known in T1D.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated a prospective clinical cohort with T1D without known cardiovascular disease. The inflammatory biomarkers soluble-urokinase-plasminogen-activator-receptor (suPAR) and interleukin-6 (IL-6) were measured. Patients were stratified by elevated/low suPAR or IL-6, or simultaneously elevated suPAR and IL-6. Primary and secondary endpoints were all-cause mortality and major adverse cardiovascular events (MACE), respectively. Cox models were adjusted for 10 Steno T1 Risk Engine variables and inflammatory biomarkers. Net reclassification improvement (NRI) and C-statistics were calculated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 962 participants (52% male, median age 50, median follow-up 13.1 years), mortality was higher in patients with elevated inflammation: 31% for elevated versus 9% for low suPAR; 30% for elevated versus 11% for low IL-6; and 50% for simultaneously elevated suPAR and IL-6 versus 5% for low suPAR and IL-6. In fully adjusted models, elevated inflammation was associated with mortality (hazard ratios [95% confidence intervals]: suPAR 2.0 [1.4–3.0, <i>p</i> < 0.001], IL-6 1.8 [1.3–2.6; <i>p </i>= 0.001], and combined 4.0 [2.3–7.2, <i>p</i> < 0.001]) and MACE (suPAR 1.9 [1.4–2.6, <i>p</i> < 0.001], IL-6 1.4 [1.0–1.8, <i>p </i>= 0.034], and combined 2.6 [1.7–4.1, <i>p</i> < 0.001]). Adding suPAR, IL-6, and their combination to the Steno T1 Risk Engine improved NRI for mortality by 61%, 53%, and 84%, respectively, whereas C-statistics improved from 0.808 to 0.829, 0.826, and 0.881, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>suPAR, IL-6, and especially their combination independently predicts all-cause mortality and MACE in T1D without known cardiovascular disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"298 3","pages":"188-199"},"PeriodicalIF":9.2,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.20108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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