Efforts to find disease-modifying treatments for Alzheimer’s disease (AD) have been largely unsuccessful. The relative lack of progress and the age-related incidence of AD suggest that modulation of aging per se may be a useful alternative treatment approach. Therapeutics aimed at preventing or reversing aging should be effective in preventing or reversing dementia and the pathology associated with progressive AD. Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. HDAC activity becomes dysregulated with age and in AD. An intriguing concept is that HDAC inhibition effectively forestalls AD pathology measured more broadly, addressing the notion that rectifying homeostatic gene expression may be the critical step in ameliorating AD pathogenesis at the earliest stage of disease initiation. HDAC inhibitors target several pathways associated with aging and AD neuropathology including loss of synaptic function, mitochondrial dysfunction, increased oxidative stress, and decreased autophagy activity. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and provide pathways for treating AD. The prevalence of neurodegenerative diseases is expected to soar with the number of elderly individuals in both developed and developing countries now rising dramatically. Efforts to find disease-modifying treatments have been largely unsuccessful. These efforts have focused mainly on identifying pathogenic mechanisms specific to each disease process. The relative lack of progress with these approaches and the age-related nature of neurodegenerative disease incidence suggests that modulation of aging per se may be a useful alternative approach for delaying the onset or retarding the progression of neurodegenerative conditions ,2. This AD is a complex heterogeneous pathology that impacts multiple aspects of neuronal physiology. The predominant hypothesis guiding AD therapeutic development for the last two decades has been that amyloid initiates a cascading series of events, including phosphorylation and aggregation of tau protein, that lead to pervasive neuronal degeneration. The repeated observation that rare early-onset familial AD mutations increase pathogenic amyloid through perturbations of beta/gamma-secretase function, promoted the notion that targeting amyloid is a potential therapeutic approach. Unfortunately, failures of a number of clinical trials have called into question amyloid as the primary therapeutic target. This demands careful reconsideration of AD disease etiology and justifies why alternative strategies for therapeutic development should be explored.Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. The gradual and escalating dysfunction of essential cellular processes could link all of the cellular AD phenotypes into a complex cascade, in which amyloid is either a late-stage effector or simply a biomarker of the disease process. In support of this view, numerous transcriptional analysis studies have examined genetic dysregulation in AD and found metabolic processes, oxidative stress, protein degradation, synaptic function and transcriptional regulation to be impacted ,6. Gene HDAC inhibition is a powerful approach to stimulate transcriptional changes within neurons. HDAC activity becomes dysregulated with age and in AD and has been shown to decrease synaptic plasticity in mouse models ,14. The Our published observations that phenylbutyrate (PBA), an HDAC inhibitor, attenuated amyloid plaque development in the PS1delta9/APPswe double transgenic mouse line and partially restored cognitive function , set theHDAC inhibitors target several pathways associated with aging and AD neuropathology. Synaptic pathology is increasingly of interest in assessing AD pathology and is linked to normal aging as well ,20. GeneClosely linked with synaptic pathology, mitochondrial dysfunction leading to decreased ATP production and increased ROS resulting from impaired electron transport chain function appears prominently in both aging and AD –30. The Autophagy plays a key role in neuronal physiology and pathology. It degrades cell organelles and misfolded proteins by fusing autophagosomes with lysosomes to prevent buildup of wastes within the cell and promote homeostasis and organelle self-renewal. Misfolded proteins can induce autophagy in primary neurons and this induction can be impaired under neurodegenerative disease conditions ,33. ExprThere is now a growing consensus that increased histone acetylation with globally elevated transcription might be beneficial at older ages as it contributes to reversion of age-dependent decline in expression of metabolic, stress response, and reparative genes involved in homeostasis and health span. There is thus a rationale for targeting deacetylation with inhibitors to activate expression of specific genes. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and enhance intervention of AD.


Esophageal atresia, diaphragmatic hernia and abdominal wall defects provide examples of congenital anomalies which have been shown to have poorer neurodevelopmental outcomes in the face of prematurity, with associated increased surgical complexity, higher relative cumulative doses of medications, longer hospital and intensive care stay and increased rates of feeding difficulties, compared with infants who experience either prematurity or congenital anomalies alone.Preterm infants are more likely to be born with congenital anomalies than those who are born at full-term. Conversely, neonates born with congenital anomalies are also more likely to be born preterm than those without congenital anomalies. Moreover, the comorbid impact of prematurity and congenital anomalies is more than cumulative. Multiple common factors increase the risk of brain injury and neurodevelopmental impairment in both preterm babies and those born with congenital anomalies. These include prolonged hospital length of stay, feeding difficulties, nutritional deficits, pain exposure and administration of medications including sedatives and analgesics. Congenital heart disease provides a well-studied example of the impact of comorbid disease with prematurity. Impaired brain growth and maturity is well described in the third trimester in this population; the immature brain is subsequently more vulnerable to further injury. There is a colinear relationship between degree of prematurity and outcome both in terms of mortality and neurological morbidity. Both prematurity and relative brain immaturity independently increase the risk of subsequent neurodevelopmental impairment in infants with CHD. Non-cardiac surgery also poses a greater risk to preterm infants despite the expectation of normal  Congenital anomalies which require surgery during the neonatal period predispose infants to brain injury and subsequent neurodevelopmental impairment, including both cardiac and non-cardiac lesions . Contribin utero or ex utero status. The impaired in utero environment may compromise brain growth and development due to placental dysfunction, uterine dysfunction, maternal ill health, infection, or injury  is a risk to term-born neonates, then the additive impact of prematurity is potentially cumulative. Hunt et al. reported the 8-year-old outcomes of three cohorts of extremely preterm infants who underwent a surgical procedure during their NICU admission . They foWalsh et al. specifically excluded congenital anomalies from a group of preterm infants less than 30 weeks gestation included in a study comparing MRI at term-equivalent age and 2-year outcome between those who did and did not receive surgery and anesthesia . A relatMost major neonatal surgery is time-critical such that pre-operative MRI is very challenging to obtain. Those researchers who have managed to obtain such images are subject to extreme bias as the more complex or unwell infants are least likely to have been able to access the MRI scanner prior to surgery. Fetal imaging would be the obvious solution to exploring brain growth prior to non-cardiac surgery but has not yet been widely explored to date.Congenital heart disease (CHD) makes up the largest cohort of infants with congenital anomalies requiring neonatal surgery and has provided a helpful model to understand the impact of impaired fetal development on the growing brain. Fortunately, cardiac anomalies often have a slightly longer window of opportunity to allow pre-operative imaging than non-cardiac surgical anomalies. Furthermore, there is an extensive literature exploring fetal MRI in this population.per se. This potential link has been confirmed by MRI studies linking cerebral oxygenation with impaired growth in fetuses with CHD  and neurodevelopmental impairment in CHD, even in early term-born infants. A study of 971 consecutive neonates with critical CHD was stratified by gestational age and adjusted for severity of lesion, against a reference group of neonates born at 39–40 weeks gestation. The risk of cerebral injury increased 2-fold in the 37–39 week gestation group; 8-fold in the 34–37 week gestation group and 25-fold in infants less than 34 weeks gestation at birth . In the  surgery . Ortinau surgery , but Bel surgery .There has been much debate regarding optimal timing of surgery for infants born prematurely with critical CHD . IntentiBoth critical CHD and non-cardiac congenital anomalies which require neonatal surgery, increase the risk of brain injury and subsequent neurodevelopmental impairment compared with healthy infants. MRI patterns of impairment suggest different mechanisms are at play between the two surgical groups, with myelination delay more prominent in the cardiac group and gyral maturation delays more common in the non-cardiac group. However, both types of lesions place the neonate at risk of further brain injury throughout their peri-operative and intensive care course. The additive burden of prematurity is complex but combines the vulnerable states of both prematurity and relative immaturity such that an increased risk of brain injury and subsequent neurodevelopmental impairment is inevitable.Many studies (including my own) have attempted to simplify and homogenize research findings, by excluding preterm infants from explorations of congenital anomalies on injury and outcome, when in fact this is exactly the group who needs the most attention. Rather than excluding infants with anomalies from studies of preterm neurodevelopment and preterm infants from studies of congenital anomalies, future studies should focus specifically on minimizing risk to preterm infants with comorbid congenital anomalies. This could include health-service research exploring the multidisciplinary team requirements to merge best practices across clinical craft groups with a patient-centered focus. Studies of the impact of developmental care practices in preterm infants could be extended into the surgical and cardiac environment. Further studies should provide gestation-based dosing for commonly used anesthetic and analgesic agents. Follow-up programs should incorporate later preterm infants than historically included, to allow for the potentially additive impact of surgical complexity.A more concerted focus on these high-risk infants should obviate the increased risk of impairment through improvements in patient-centered, developmentally appropriate care, which carefully balances pain management, nutritional support and brain-protective strategies from fetal or neonatal diagnosis to childhood and beyond.


Benefits of the stay-at-home order imposed in Italy to prevent SARS-CoV-2 transmission need to be weighed against its impact on citizens’ health. In a country with a solid familial culture and where welfare relies on households, confinement drastically decreased support provided by elder relatives, which may have worsened mental health.A web-based cross-sectional study  was conducted on a representative sample of Italian adults during lockdown (27th of April-3rd of May 2020). We asked 3156 subjects to report on reduced help in housework and childcare from retired parents to assess confinement impact on mental health through validated scales before and during the lockdown.Overall, 1484 (47.0%) subjects reported reduced housework help from parents, and 769  diminished babysitting support. Subjects reporting reduced housework help had worsened sleep quality  and quantity , depressive  and anxiety symptoms , compared to those reporting unreduced help. Worsening in sleep quality  and quantity , depressive  and anxiety symptoms  was also associated with reduced babysitting help. In subjects with poorer housing and teleworking, mental health outcomes were worse.Confinement came along with reduced familial support from parents, negatively impacting mental health. Social networks and support within families provided by older relatives act as a resilience factor and a potential vulnerability that affects mental health outcomes. Health and social services response should be designed to address mental health needs and mitigate long-term health costs caused by the pandemic's unprecedented stressfulness and unknown duration.National lockdown measures came along with reduced housework help supply for a large proportion of adult parents who presented increased mental health symptoms with unsatisfactory quality of life.A global, multi-level socioeconomic interdisciplinary approach is needed to inform evidence-based family and welfare policies and prevention strategies centred on population wellbeing.


The topic of older adult loneliness commands increasing media and policy attention around the world. Are surveys of aging equipped to measure it? We assess the measurement of loneliness in large-scale aging studies in 31 countries. In each country, we document available loneliness measures, examine correlations between different measures, and assess how these correlations differ by gender and age group. There is substantial heterogeneity in available measures of loneliness across countries. Within countries with multiple measures, the correlations between measures are high (range .38-.78). Differences by age and gender group are relatively small. Correlations between loneliness measures and living alone and being without a spouse are positive and similar in magnitude across countries, supporting construct validity. We establish that even single-item measures of loneliness contribute meaningful information in diverse contexts, with reliable and consistent measurement properties within many countries.


In utero exposure to maternally-derived antigens following chronic infection is associated with modulation of infants ‘immune response, differential susceptibility to post-natal infections and immune response toward vaccines. The maternal environment, both internal (microbiota) and external  also modulates infant's immune response but also the clinical phenotype after birth. Vertical transmission of ubiquitous respiratory pathogens such as influenza and COVID-19 is uncommon. Evidence suggest that in utero exposure to maternal influenza and SARS-CoV-2 infections may have a significant impact on the developing immune system with activation of both innate and adaptive responses, possibly related to placental inflammation. Here in, we review how maternal respiratory infections, associated with airway, systemic and placental inflammation but also changes in maternal microbiota might impact infant's immune responses after birth. The clinical impact of immune modifications observed following maternal respiratory infections remains unexplored. Given the high frequencies of respiratory infections during pregnancy , the impact on global child health could be important. On the other hand, a decreased expression of placental TLR mRNA (TLR 6 and 7) was observed along with suppression of pro-inflammatory placental cytokines production (IL-1 and TNF). Different knock-out experiments using TLR deficient mice suggest a critical role of maternal TLR signaling in the protection against asthma in their progeny.The factors associated with farm exposure and modulation susceptibility to atopic disease is likely multifactorial . Animal  progeny . This prOverall these data indicate that prenatal exposure to a specific maternal microbial respiratory environment is associated with modification of immune responses at birth with a potential clinical impact during infancy.Lactobacillus exposure through maternal supplementation led to decreased Th2 cytokines and lung inflammation following RSV infection in their neonates . Fetal immune cells show signs of activation as assessed by TNF-α and IFN-γ production. Immune activation is probably non-specific as no sign of SARS-CoV-2 sensitization, has been observed , possibly related to alveolar macrophages dysfunction . StudiesWe have reviewed the different mechanisms associated with acute maternal respiratory infections that could possibly impact infant's immune responses.Previous research in the field of allergy and chronic maternal infections have highlighted the impact of maternal exposure to specific microbial respiratory environment and immune modulation related to chronic infections on infant's immune responses. Susceptibility toward infection and response to vaccines in infancy are modulated after exposure to chronic maternal infection, without vertical transmission while susceptibility toward immune-mediated diseases  is impacted by the respiratory maternal environment , 8, 19.in utero sensitization seems infrequent after exposure to maternal respiratory infections such as influenza and COVID-19.In this mini-review, we show that part of these mechanisms are also observed during maternal respiratory infections, namely induction of innate immune responses and placental inflammation. On the other hand, Maternal microbiota editing may also have an impact on infants ‘immune responses. During pregnancy, disturbance in the mother microbiota either as a result of infection or stress linked to sexual hormones might influence infant health through several ways. Following lung-gut microbiota crosstalk, additional effects may be associated with upper respiratory infections during pregnancy. Alterations in the lung microbiota profile have been associated with several respiratory diseases such as pneumonia or viral infection . DysbiosMaternal respiratory infections such as influenza and COVID-19 are associated, beside upper and respiratory tract inflammatory responses, with systemic and placental inflammatory responses. Studies performed during the COVID-19 pandemic indicate that neonates exposed to respiratory infections have distinct innate but also adaptive responses, independently of virus-specific immune activation, as sensitization appears infrequent –33. ResuModulation of placental TLR responses is associated with differential risk of atopic diseases during infancy. The impact of maternal influenza or COVID-19-induced placental inflammation on the risk of atopic diseases during infancy is undetermined.Finally, responses to vaccines at birth or during infancy, might also be impacted following disturbances of both adaptive and innate immune responses, as previously shown following chronic maternal infections with protozoans or helminths , 7. NotaMost of the literature reviewed here was related to influenza and COVID-19. Other respiratory infections such as RSV and human metapneumovirus (HMPV) are highly prevalent worldwide and also reported during pregnancy as causes of acute respiratory illnesses –56. MoreMaternal vaccination is recommended during pregnancy for both influenza and COVID-19; whether maternal vaccination is associated with dampening of inflammatory immune response following respiratory infection remain to be demonstrated.


The task switching paradigm is widely used to examine cognitive switching, a critical subcomponent of cognitive control. Studies on aging suggest that switching is particularly vulnerable to age-related changes in cognition. However, the effects of manipulating the stimulus dimension on task switching performance is relatively understudied. In this study, 13 younger adults  and 13 older adults  completed a novel cued task-switching paradigm requiring speeded same-different judgments based on a perceptual (color) or conceptual  dimension of the stimuli. Task switching performance was measured using switch cost, which is the difference in accuracy between switch and repeat trials. Overall both YA and OA exhibited switch costs, indicating increased cognitive demand when switching between judgments compared to repetition of the same judgement. In regard to group differences, YA and OA performed similarly when performance was collapsed across the stimulus dimensions; however, when examined separately, OA exhibited worse performance than YA when making conceptual judgements. These results highlight the importance of examining carefully manipulated stimulus-related factors in task switching paradigms to advance our understanding of cognitive control and aging.


Health-related behavior correlates in critical ways with the current epidemic of chronic diseases. Modifiable behaviors increase the risk of chronic disease. Despite there are well-identified behaviors, efforts at behavior change are clinically-challenging and frequently ineffective.We aim to establish how the current evidence and latest neuroscientific knowledge about behavioral change allow the most reliable assessment of patients with refractory health-related behaviors that negatively impact health outcomes.We performed a literature review using Pubmed databases and UpToDate. The search included “behavioral change” and “health-related behavioral change”[MeSH Terms].Habitual behavior consists of behavioral patterns operating below conscious awareness and acquired through context-dependent repetition. Behavioral change is a complex multi-level field of intervention. The Health Belief Model allows a careful description of the patient’s perceived vulnerability, perceived disease severity, self-efficacy, and change motivation. The identification of social variables is critical since they correlated with poor health outcomes, particularly in chronic diseases. Temperament and character traits can have a strong influence on the difficulty of changing habitual behavior. Psychopathology, if present, must be addressed because it can be a notable factor of behavior instability and correlates negatively to health outcomes. Assertive and efficient communication skills in the clinical context are imperative. Motivational interviewing skills can allow effective behavioral change.Interventions addressing behavior change require careful, thoughtful work that leads to a deep understanding of the nature of what motivates people. Intervention based strategies focused on behavioral change must undergo further investigation in the future.No significant relationships.


Lo non-classical monocytes promotes resolution of perinatal liver injury in a murine model of perinatal hepatic inflammation. Our research also identifies a potential co-regulatory role between neutrophils and non-classical monocytes. Further work is needed to understand how neutrophils regulate other myeloid populations during perinatal liver inflammation. Elucidating the mechanisms that govern perinatal liver injury and repair may lead to the development of immune-directed therapies that can be used to mitigate the devastating effects of diseases like BA.Perinatal liver inflammation can have life-threatening consequences, particularly in infants and young children. An example of a hepatic inflammatory disease during infancy is biliary atresia (BA), an obliterative cholangiopathy that rapidly progresses to hepatic fibrosis and liver failure. The aggressive nature of BA in neonates compared to the pathogenesis of inflammatory liver diseases in adults, suggests that the mechanisms responsible for restoring tissue homeostasis following inflammation are impaired in affected infants. This article reviews our recent findings demonstrating that the relative abundance of Ly6c The maturation of the immune system is a complex process that undergoes major transitions during fetal and neonatal development . ThroughLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation,” we demonstrate the importance of monocyte subsets in mitigating inflammatory insults to the perinatal liver. Using a rhesus rotavirus (RRV) model of perinatal liver injury, we investigated changes in composition of the hepatic myeloid immune compartment in late-gestation fetuses and in neonatal pups [Lo non-classical monocytes observed at this time. Since Ly6cLo non-classical monocytes exert anti-inflammatory and pro-reparative functions [In our recent study, “Ly6ctal pups . Our iniunctions –7, we hyLo non-classical monocytes. Using anti-Ly6g targeted neutrophil depletion [Hi classical monocyte depletion [Lo non-classical monocytes within RRV-injected neonatal livers. Importantly, antibody-mediated depletion of neutrophils and Ly6cHi classical monocytes increased both the percentage and the absolute number of Ly6cLo non-classical monocytes, indicating both a proportional and numerical expansion of these cells. Furthermore, the rise in Ly6cLo monocytes was associated with disease resolution in the neonate, supporting the idea that Ly6cLo non-classical monocytes play a role in resistance to perinatal liver injury and resolution of disease. To confirm Ly6cLo non-classical monocytes are responsible for disease resolution and resistance [Lo non-classical monocyte function in the setting of neutrophil and classical monocyte depletion [Lo non-classical monocytes mitigate perinatal liver inflammation [To test this hypothesis, we manipulated the myeloid compartment within the neonatal liver to resemble the fetal environment, thereby establishing an abundance of Ly6cepletion , and antepletion , we expasistance , we usedepletion –12. Blocammation .Lo non-classical monocytes [Lo non-classical monocytes reveals a co-regulatory relationship between these two cell populations that are important for tissue repair and healing [Recent evidence suggests that neutrophils play a vital role in regulating and orchestrating inflammation and tissue repair through their interaction with the innate and adaptive immune systems –16. Seveonocytes , suggest healing .An intriguing mechanism by which neutrophils may influence other myeloid populations during inflammation may involve the regulation of myeloid precursors and hematopoietic progenitors . We haveThe liver is known to serve as the primary hematopoietic organ throughout fetal life as it harbors the hematopoietic stem cell (HSC) niche . Soon afHi myeloid cells, and Ly6cLo and Ly6cHi monocytes in the setting of tissue injury and systemic disease [In addition to the liver, the spleen can also contribute to the overall hematopoietic activity during neonatal development and inflammation via EMH ,36. Howe disease ,38. ThesUnderstanding the immune response to liver injury during perinatal development is particularly important as the dynamic transitions in hematopoiesis during this time may establish a unique environment that is susceptible to injury and inflammation. Since the liver and spleen are believed to contribute to hematopoiesis in the setting of perinatal liver inflammation, it is important to understand the kinetics of neonatal emergency hematopoiesis to highlight the possible mechanisms by which myeloid populations may contribute to liver injury and repair. Insights gained into perinatal liver inflammation mechanisms will undoubtedly lead to tailored therapies for infants and children who suffer from the devastating consequences of perinatal liver injury.


Immune checkpoints are small molecules present on the cell surface of T-lymphocytes. They maintain self-tolerance and regulate the amplitude and duration of T-cell responses. Antagonism of immune checkpoints with monoclonal antibodies (immune checkpoint inhibitors) is a rapidly evolving field of anti-cancer immunotherapy and has become standard of care in management of many cancer subtypes. Immune checkpoint inhibition is an effective cancer treatment but can precipitate immune related adverse events (irAEs). Thyroid dysfunction is the most common endocrine irAE and can occur in up to 40% of treated patients. Both thyrotoxicosis and hypothyroidism occur. The clinical presentation and demographic associations of thyrotoxicosis compared to hypothyroidism suggest unique entities with different etiologies. Thyroid irAEs, particularly overt thyrotoxicosis, are associated with increased immune toxicity in other organ systems, but also with longer progression-free and overall survival. Polygenic risk scores using susceptibility loci associated with autoimmune thyroiditis predict development of checkpoint inhibitor associated irAEs, suggesting potentially shared mechanisms underpinning their development. Our review will provide an up-to-date summary of knowledge in the field of thyroid irAEs. Major focus will be directed toward pathogenesis (including genetic factors shared with autoimmune thyroid disease), demographic associations, clinical presentation and course, treatment, and the relationship with cancer outcomes. Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of medications. At present, over 2000 clinical trials have been completed or are in progress to evaluate more than 30 different ICIs . The maiImmune checkpoints are small molecules present on the cell surface of T-lymphocytes . NormallThe etiology of irAEs is yet to be fully elucidated. Potential mechanisms include activation of polyclonal T-cell populations, loss of regulatory T-cell function, and expansion/activation of self-reactive, antigen-specific T-cells . IrrespeThyroid irAEs are the most common endocrine toxicity related to ICI-treatment . From clThyroid irAEs are typically identified incidentally during routine monitoring of thyroid function as part of ICI-treatment protocols . Most thOnset of thyrotoxicosis usually occurs within 3 months of first ICI-exposure , 7. OverIsolated hypothyroidism without a preceding thyrotoxic phase can occur. Most cases of isolated hypothyroidism are biochemically subclinical and may be related to non-ICI factors such as non-thyroidal illness syndrome. Subclinical hypothyroidism without a preceding thyrotoxic phase typically normalizes spontaneously without need for thyroid hormone replacement , 15. OveIdentification of reliable thyroid irAE risk factors has been elusive. To date, no reliable risk factors of thyroid irAEs have been identified, although clinical and biochemical associations have been documented in retrospective cohort studies . Female The etiology and biological drivers of irAEs remain elusive. It is possible that patients who experience irAEs may share a premorbid immunological state prior to ICI-initiation. A recent study using mass cytometry time of flight analysis identified higher levels of activated CD4+ memory T-cells and increased diversity in the T-cell receptor as pretreatment predictors of severe irAEs irrespective of the organ involved . These svia multiple mechanisms as evidenced by phenotypic differences in presentation, antithyroid antibody positivity rates, and differential association with cancer survival outcomes  thyrotoxicosis to biphasic thyroiditis to isolated overt and severe hypothyroidism. This indeed may be the case, although more likely thyroid irAEs arise outcomes .Genetic factors associated with lifetime risk of autoimmune thyroid disease have been implicated in the risk of developing thyroid irAEs during ICI-treatment , 22. Keyvia and therefore thyroid dysfunction is more rapidly progressive following ICI-treatment than in other autoimmune thyroid conditions  should have TSH-receptor antibody level (TRAB) measured to exclude Graves’ disease . In sevePatients with established hypothyroidism may experience transient effects on thyroid function following ICI-treatment . Compensde novo related to ICI-treatment, is unmasked by ICI-treatment, or is a coincidental occurrence remains unknown. Similarly, thyroid eye disease (TED) has been reported (Graves’ disease (GD) has been reported following ICI-treatment . Whetherreported . ReactivObservational studies repeatedly document an association between irAEs and improvement in cancer outcomes , 30. OwiInterestingly, abnormal TSH level (elevated or low) prior to initiation of ICI-treatment has been associated with inferior cancer outcomes irrespective of thyroid function changes post-ICI initiation in one study . HoweverFurther research is required to better inform our understanding of thyroid irAEs and their relationship to thyroid autoimmune conditions occurring outside the cancer immunotherapy setting. Enhanced characterization of the immune phenotype and T-cell subsets driving thyroid irAEs may allow for identification of patients at risk of thyroid (and other) irAEs and inform future research to uncouple the efficacy of ICIs from the risk of developing treatment related irAEs. Understanding the effects of immune checkpoint inhibition on the thyroid gland could also inform use of these agents for treatment of primary thyroid malignancies and prevention of autoimmune thyroid disease.Thyroid irAEs are a frequent complication of anti-PD-1 based ICI-treatment. Recent work has begun to unravel the molecular mechanisms underpinning development and their relationship to other autoimmune thyroid conditions. Regular monitoring of thyroid function during ICI-treatment is required, as although most cases of thyroid irAEs are asymptomatic and manageable, severe presentations with thyroid storm or myxedema can occur. Development of thyroid irAEs is associated with improved PFS and OS, especially overt thyrotoxicosis which may be a surrogate marker of patients experiencing a more robust immune response to ICI-treatment. When hypothyroidism occurs, it is usually permanent and treatment with thyroid hormone replacement will be required. Familiarity with thyroid irAEs among health professionals is important to facilitate efficient diagnosis and appropriate treatment of this increasingly common thyroid disease.All authors listed have made a substantial, direct, and intellectual contribution to the work. All authors approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Systemic amyloidosis is a diseased condition where misfolded proteins deposit in various organs in the form of amyloids, and transthyretin deposition, termed ATTR amyloidosis, can be either an age-related amyloid formation from misfolded wild-type TTR (ATTRwt) or by hereditary TTR malfunction due to mutation in the TTR gene (ATTRv). Although ATTRwt amyloidosis can cause various diseases, such as cardiac failure, conduction disturbances, arrhythmias and carpal tunnel syndrome, it is still under-recognised considering its clinical significance. Here the authors report a case of ATTRwt amyloidosis leading to carotid stenosis requiring surgical intervention. To the best of our knowledge, the current report is the first that described histopathological evidence of amyloid deposition in the carotid artery due to ATTRwt amyloidosis. TTR gene (ATTRv) [Systemic amyloidosis refers to a diseased condition where misfolded proteins deposit in various organs in the form of amyloids . Various (ATTRv) . Althoug (ATTRv) . Here thA 77-year-old Japanese male with a past medical history of acute cardiac infarction was diagnosed with a right carotid artery stenosis which progressed in three years . A digitThe hematoxylin and eosin-stained surgical specimen revealed carotid intima’s eccentric fibrosis, compatible with arteriosclerotic change . Masson’Amyloid cardiomyopathy refers to the myocardial deposition of amyloid fibers causing cardiac dysfunction, and it comprises AL  amyloidosis and ATTR amyloidosis . AlthougOn the other hand, ATTR amyloidosis was considered a much infrequent rare condition compared with AL amyloidosis. However, extensive research has been pursued on ATTR amyloidosis due to its clinical significance in heart failure and it has recently been reported that amyloid deposits derived from plasma transthyretin are present in the heart of up to 25% of elderly individuals . Tafamid


Bi-directional associations between depression and cognitive functioning are magnified among aging individuals, challenging behavioral health providers who treat older adults experiencing clinical and subsyndromal depression. This symposium contributes to the science and practice of assessing and treating later-life depression while also attending to issues in professional training. The first paper presents pre-treatment data from the multi-site Optimum Study of older adults experiencing treatment-resistant depression (n = 529). The relevance of positive psychological constructs is supported with analyses showing important relationships among cognitive functioning, social participation, and psychological well-being. The second paper describes the development of an updated measure to assess behavioral health providers’ knowledge of later life depression, including brain health concerns. Psychometric data for the measure were generated from a random pool of licensed social workers (N=900) who were mailed the survey packet. The third presentation features an experimental study demonstrating that foundational information about aging, including debunking misconceptions about cognitive aging, influenced continuing education preferences of generalist Licensed Professional Counselors (LPCs). Among the randomly generated pool of LPCs (N = 120), participants who received aging-specific information were more likely to later choose an aging-specific continuing education option. The fourth paper highlights recommendations for mental health practitioners working in primary care and general medical settings with older adults who have co-existing depressive symptoms and cognitive concerns. The fifth and final presentation describes cognitive behavioral clinical tools to address brain health concerns in the context of later-life depression, using the new Brain Health module of a published client workbook.


While a growing body of evidence points to potentially modifiable individual risk factors for Alzheimer’s Disease and Related Dementias (ADRD), the contexts in which people develop and navigate cognitive decline are largely overlooked. Geographic variation in ADRD rates suggest that environmental risk and protective factors may be important in cognitive aging and dementia caregiving. Community hazards are often heavily concentrated in underserved and underrepresented neighborhoods. This symposium aims to identify specific built, social, and natural environmental features associated with cognitive aging outcomes. The papers provide much-needed evidence on the role of neighborhoods and community networks for cognitive health and well-being among diverse older adults. First, Godina finds significant associations between neighborhood greenspace and microstructural indicators of brain health. Second, Westrick investigates the role of neighborhood disadvantage on long-term memory aging of older adults with and without a cancer diagnosis in later-life. Third, Finlay presents a new concept of Cognability to demonstrate which constellation of positive and negative neighborhood features may contribute most to healthy cognitive aging. Fourth, Nkimbeng identifies community networks and resources needed to inform dementia education and support care among African immigrants. Fifth, expert discussant Besser will share how these findings may inform upstream health promotion and reduce ADRD risk. She will discuss critical future research directions and methods to investigate environments of cognition. The symposium advances research assessing contexts of aging, and may inform public health and policy efforts to ameliorate community barriers and create more equitable opportunities to promote healthy aging in place.


Fall risk assessment traditionally focuses on objective physical performance. Balance confidence, a subjective measure of physical function, may provide important information to better predict fall risk and guide assessment and intervention strategies. This study examines the associations of balance confidence congruency with physical performance measures and fall occurrence. One-hundred-fifty-five community-dwelling adults aged 60 and over completed a comprehensive fall risk assessment including physical performance tests , activities-specific balance confidence (ABC) scale, and self-reported falls in the past year. Four groups were created based on congruency between balance confidence (low vs. high) and each physical performance measure or overall fall risk category . Poison regression analyses, adjusted for age and gender, tested the association between group membership and number of falls in the past year. Participants with high balance confidence and at fall risk based on 4-stage balance performance , or high balance confidence and at fall risk following the STEADI screening algorithm  were at increased risk of more falls compared to participants in the group with high balance confidence and not at fall risk. These results suggest that older adults who overestimate their balance relative to their physical performance may be at increased fall risk, and that participant subjective reporting of physical performance should be paired with objective physical performance measures to better identify older adults at fall risk.


Maintaining a sense of purpose promotes mental and physical well-being in older adults . Drawing on one’s sense of purpose is thus important for late life resilience. How older adults’ sense of purpose manifests in their everyday lives remains understudied. This study used qualitative methods to amplify older adults’ voices regarding purpose and resilience through analysis of their life stories. This study 1) explored what factors contribute to maintaining purpose in older adulthood, and 2) identified how older adults draw on their purpose during major challenges, particularly in the context of the COVID-19 pandemic. Eighteen older men and women  participated in semi-structured life story interviews that asked about participants’ individual interpretations of purpose in their lives and their experiences navigating the COVID-19 pandemic. Thematic analysis was conducted using established methods . To address the first research question, analyses revealed that older individuals largely maintain their purpose through engaging in acts of service to others, fostering connections with close others, and actively setting and achieving goals. Regarding the second question, older adults described how drawing on purpose through acts of service and connections with others fostered resilience through the COVID-19 pandemic. Overall, older adults’ own expressions of their life stories illuminated how they are guided by purpose. Findings demonstrate the functionality of purpose in late life and how purpose can be practically fostered, specifically within the context of universally challenging experiences such as the COVID-19 pandemic.


Despite the benefits of palliative and end-of-life (PEOL) care for individuals with life-limiting illness, barriers to accessing this care persist among older adults experiencing homelessness. A number of studies have identified barriers to PEOL care from the perspectives of unhoused individuals and other relevant stakeholders; however, few empirically studied interventions exist to support evidence-based guidelines for PEOL care for this population. This scoping review aimed to identify PEOL interventions for adults experiencing homelessness. The search was conducted in May 2021 and yielded 480 results, from which 50 full-text articles were closely reviewed for inclusion. Sources were included if they reported findings of original, empirical research or quality improvement projects evaluating PEOL services tailored for individuals experiencing homelessness. A total of 13 articles representing 12 studies published between 2006-2021 were included in the review. Over half (n = 7) of the studies described interventions to promote advance care planning documentation, five described interventions embedding PEOL services within homeless shelters, and one described a community outreach program to increase access to PEOL services. Nearly all studies reported positive outcomes on participant perspectives, advanced directive completion rates, or cost analysis. None of the studies included clinical palliative care outcomes. Although most studies reported promising results, service and healthcare providers expressed concerns about continuing challenges and longevity of the programs. The body of literature encompassing PEOL interventions for people experiencing homelessness is limited but growing. Future research may benefit from the inclusion of clinical outcomes and efforts to reduce structural barriers to providing care.


Healthcare systems have become complex and fragmented, negatively affecting healthcare access and navigation. This is especially the case for socio-economically vulnerable people, who encounter organisational and administrative hindrances trying to access care. These difficulties have worsened during Covid-19. Scholarly literature recognises that - by moulding navigation practices - social capital may mediate between potential and realised access to healthcare. However, little is known about how this mediating work practically unfolds.This case study aimed to understand how social capital might affect healthcare navigation practices. To do so, we investigated how the People’s Health Lab (PHL), a community-based organisation, supported socio-economically vulnerable people in navigating healthcare during the Covid-19 pandemic in Bologna, Italy. Nine months of participant observation were conducted both in person and digitally from July 2020 to March 2021. Twelve semistructured interviews were also conducted with volunteers of the organisation. Fieldnotes and interview transcripts were analysed through Thematic Analysis.PHL support activities addressed barriers to healthcare navigation by vulnerable people, which were found to be services fragmentation, bureaucracy and Covid-19 restrictions. Volunteers of the PHL connected vulnerable individuals to health services in manifold, flexible ways, working without standard operative protocols and relying on informal personal contacts within public services. This was found to be key in enabling navigation of healthcare during the first three waves of the pandemic.Our study provides evidence about how structural, linking social capital - the material and nonmaterial resources mobilised through the relationships between heterogeneous groups  - can mediate access to fragmented healthcare systems by shaping navigation practices.• Contemporary healthcare systems – including universal ones – have become complex and fragmented, posing access and navigation challenges to their users, especially those socio-economically vulnerable.• Linking social capital can mediate access to fragmented healthcare systems by flexibly mobilising material and nonmaterial resources through informal relationships between heterogeneous groups.


Cancer immunotherapy has gained significant attention in recent years and has revolutionized the modern approach to cancer therapy. However, cancer immunotherapy is still limited in its full potential due to various tumor immune-avoidance behaviors and delivery barriers, and this is seen in the low objective response rates of most cancers to immunotherapy. A novel approach to immunotherapy utilizes image-guided administration of immunotherapeutic agents directly into a tumor site; this technique offers several advantages, including avoidance of potent toxicity, bypassing the tumor immunosuppressive microenvironment, and higher therapeutic bioavailability relative to systemic drug administration. This review presents the biological rationale for locoregional image-guided immunotherapy administration, summarizes the existing interventional oncology approaches to immunotherapy, and discusses emerging technological advances in biomaterials and drug delivery that could further advance the field of interventional oncology. Immunotherapy with immune checkpoint inhibitors has revolutionized cancer care by stimulating the body’s adaptive immune system to detect, engage, and eliminate cancerous cells . Recent The field of interventional radiology is well-poised to drive innovation in cancer immunotherapy. Image-guided interventions have already been used to establish several novel and minimally invasive approaches to cancer treatment, including radiofrequency/thermal tumor ablation, trans-arterial chemoembolization, and targeted delivery of yttrium-90 (Y-90) emitting microspheres . These tThe basis of cancer immunotherapy lies in transforming the adaptive immune system to be able to recognize and eliminate previously unrecognizable tumor tissue, resulting in sustained antitumor activity from the body’s natural immune mechanisms. Current approaches utilize immunotherapy alone as well as in conjunction with conventional chemotherapeutics/radiation depending on the type and stage of tumor . In a tyA significant barrier to this natural process is the ability of tumor cells to evade detection by the immune system and downregulate the cellular immune response. Various mechanisms are utilized by cancers to prevent immunogenicity, ranging from intrinsic regions of hypoxia and elevated lactate levels to production of immunosuppressive cytokines that directly deactivate T cell responses . AdditioLocoregional delivery of immunotherapy utilizing interventional oncology approaches can avoid many of the obstacles associated with current immunotherapy approaches. Using image guidance from X-ray fluoroscopy, ultrasound, magnetic resonance imaging, or computed tomography, an interventional radiologist can utilize a vascular or percutaneous approach to a tumor site and selectively administer immunotherapy directly within a tumor. One significant benefit to this approach is limited off-target effects/systemic toxicity as the therapeutic remains localized within the tumor site. This also allows for lower therapeutic doses to be delivered while concurrently achieving a higher drug concentration within tumors. Another major advantage is the ability to effectively handle metastatic lesions by individual targeting of tumors and immune system potentiation, potentially sparing the patient from systemic effects . The objAs previously described, the immunosuppressive tumor microenvironment poses a significant challenge to both traditional anticancer and novel immunotherapy approaches, so the key goal of immuno-oncology remains to induce the immune system despite these barriers. Tumor ablation and the resulting immune activation from the necrosis-associated DAMPs has proven to be a viable mechanism for this strategy and several techniques are already widely utilized in clinical practice by interventional radiologists to cause tumor immunogenic cell death. Endovascular therapies such as trans-arterial chemoembolization (TACE) and trans-arterial radioembolization (TARE), percutaneous methods including radiofrequency ablation (RFA) and cryoablation, and stereotactic laser-guided approaches have demonstrated tumor volume reduction with consequent immune activation, and immunotherapy can be utilized similarly alongside these techniques for synergistic therapeutic effects .Oncolytic virotherapy is a novel technique that re-engineers human viruses for cancer destruction and DAMP production. The drug talimogene laherparepvec  is the first and at present only FDA approved intratumoral immunotherapy and is used to treat advanced melanoma. TVEC utilizes an attenuated herpes simplex virus, type 1 (HSV-1) which has been engineered to produce granulocyte-monocyte colony stimulating factor (GM-CSF); the double stranded DNA virus can directly and preferentially lyse tumor cells, producing DAMPs and activating the previously latent adaptive immune system. TVEC has demonstrated a well-tolerated and durable response rate in a 2015 Phase III clinical trial, although 5-year survival remained low with monotherapy . ClinicaAdditionally, several other viruses have been identified to have oncolytic properties, including adenovirus, poliovirus, measles virus, and coxsackievirus; though these therapeutics are still in early clinical trials, they have demonstrated oncolytic ability in preclinical models and could open up new therapeutic avenues against a wide range of malignancies . NotablySystemic administration is the conventional approach for oncolytic virus delivery but therapeutic outcomes against solid tumors continue to be modest . The maivia intratumoral delivery as well.Checkpoint inhibitors have proven to be one of the most transformative advances in modern immunotherapy. The immunosuppressive checkpoints mentioned earlier  can be blocked by therapeutics to allow for a more potent immune response, and several drugs have received FDA approval for use against various solid and hematologic malignancies . Pembrolvia the cyclic GMP–AMP synthase (cGAS) – stimulator of interferon genes (STING) pathway. Activation of these pathways promotes transcription of pro-inflammatory cytokines and interferons which can allow for more potent antitumor responses   cells can contribute to tumor elimination by phagocytosis and cytotoxic mechanisms. The innate immune system is especially sensitive to external antigens, with dedicated sensing pathways for bacterial toxins  and nucleic acids esponses . Therape2668770) . Similar2668770) . HoweverCAR-T cells, which are T cells engineered for anti-cancer activity, have demonstrated significant activity against various types of hematological malignancies. Multiple formulations of systemic CAR-T cell therapeutics have received FDA approval for use against B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma . HoweverNanoparticle-mediated drug delivery is rapidly gaining popularity in clinical applications and may offer solutions to delivery limitations imposed by the immunosuppressive tumor microenvironment. Nanoparticles are defined as materials with a size range between 1 and 100 nm and can be synthesized from a variety of materials, including lipids, polysaccharides, and inorganic compounds. These structures can encapsulate therapeutics and be engineered to navigate biological barriers and deliver their payload to a disease site in a controlled, targeted fashion . Though via T cell targeting nanoparticles achieved stronger T cell activation than systemic administration of the therapeutic in mouse models. Lipid nanoparticles containing a TGF-β inhibitor were synthesized with anti-CD8 antibodies conjugated to the particle surfaces and injected into mice expressing B16 melanoma, achieving high concentrations in tumor sites. The group further demonstrated the ability to specifically target tumor reactive lymphocytes by conjugating anti-PD-1 antibodies to the particle surfaces  against the fibrinogen-like protein (FGL1) gene; the nanoconstructs aimed to deliver metformin to block PD-L1 to prevent T cell suppression while simultaneously using siRNA against FGL1 to block another anti-inflammatory pathway. Of note, a pH trigger was utilized in these nanoparticles as the reaction of metformin with CO2 results in the low-pH-activated endosomal escape of the nanoparticle payload. l groups .in vitro and in vivo cellular penetration in preclinical studies, and clinical trials may soon be possible with these novel therapeutics (These studies highlight the ability to engineer nanosystems for targeted delivery and demonstrate a clear potential for applications of nanoparticle technology in cancer immunotherapy. Basic science and clinical research in nanoparticles is highly active with many promising developments on the horizon. Magnetic biomaterials such as iron oxide nanoparticles are being explored for magnetic hyperthermia, a technique which oscillates nanoparticles in an alternating magnetic field to cause heat-induced death and DAMP generation of tumor tissue. Magnetic nanoparticles can also be engineered for highly precise targeting to tumor sites along with magnetic-mediated drug delivery and cellular uptake . CRISPR-apeutics . Technolapeutics . Image-gThe field of interventional oncology as a whole is burgeoning with technological and clinical advancements, and many of the discipline’s most impactful discoveries are just starting to show their promise. Intratumoral administration of cancer immunotherapy in particular has significant potential to alter the landscape of cancer treatment in the coming years, both independently and in conjunction with conventional treatment strategies. Many treatment-resistant or difficult-to-reach malignancies could become accessible with further advances in locoregional therapeutic administration. Moreover, the exciting developments in biomaterials and biotechnology will further enhance the precision and efficacy of locoregional immunotherapy. It is important to keep in mind that many of these technologies are still being validated in preclinical models or early-stage clinical trials and are still several years away from seeing widespread therapeutic applications in humans. However, the promising results demonstrated by the various studies covered in this review and beyond signal high and rapidly growing interest and expectations for a revolutionary approach to cancer treatment from scientists, clinicians, and patients.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Worse physical and mental health are risk factors for cognitive decline in older adults. In Puerto Rico, existing healthcare services are lacking, further exacerbating this risk. This study examines how mental and physical health factors affect subjective cognitive decline for older adults in Puerto Rico. Data comes from the 2020 Behavioral Risk Factor Surveillance System, restricted to adults age 60+ residing in Puerto Rico (n = 1603). Subjective cognitive decline was measured with two dichotomous variables (no/yes): increases in confusion or memory loss and difficulty making decisions in the past year. Multivariate logistic regression models were run for each outcome variables. Predictor variables were number of days in past month with poor mental health, diagnosis of depression or mood disorder, self-rated health, and access to healthcare services, along with covariates. Higher number of days with poor mental health , diagnosis of depression or mood disorder , and cost barriers to accessing healthcare  were associated with increased odds of increased confusion or memory loss. Significant predictors of increased odds of decision-making difficulty included higher number of days of poor mental health , diagnosis of depression or mood disorder , and worse self-rated health . To promote better cognitive health, intervention efforts should focus on those with poor mental and physical health, including identify strategies to improve access to healthcare services.


Normal respiratory functioning is essential for survival. Injuries or obstructions to airways, lungs or respiratory neural networks can have catastrophic consequences. Every breath places the lungs at the mercy of environmental air quality, which can contain pollutants, noxious gasses, and pathogens, driving or exacerbating acute and chronic respiratory conditions. Airway inflammatory diseases can compromise airflow through excessive mucus and airway wall edema, remodeling, and/or bronchoconstriction. Glottic proximity to the esophagus makes aspiration  a constant threat. Indeed, aspiration frequently causes pneumonia and can lead to sudden, lethal airway obstructions. Neurological trauma or pathology may interfere with respiratory processes, with dire consequences for breathing and airway clearance. While impaired sensory function is problematic, so too is hypersensitivity, contributing to conditions such as chronic cough.It is therefore unsurprising that the respiratory system is equipped with many precise defensive mechanisms that collectively safeguard against risks, but our understanding of these processes is incomplete. This research topic brings together established experts and emerging future leaders to describe the state-of-the-art understanding of pulmonary defenses in health and disease, paving a direction for future research.Lin et al.). Interestingly, select RARs responded immediately, an effect mediated by 5-HT3 receptors, known to be expressed by some vagal sensory neurons .The respiratory system contains diverse sensory nerve fibers that monitor the physical and chemical environment of the airways and lungs. Subsets of mechanosensitive fibers, the slowly (SARs) and rapidly (RARs) adapting receptors, respond to changes in airway smooth muscle tone and distension and lung volume, providing essential volume-related feedback to brainstem neural networks governing breathing and autonomic neural control. Lin et al. performed single unit RAR and SAR recordings in anesthetized rats, observing that serotonin administration profoundly altered RAR firing, although the response was often delayed and hypothesized to occur secondary to serotonin-induced changes in pulmonary mechanics . Mazzone et al. presented new insights into the potential role of neuroimmune mechanisms in sensory nerve plasticity: a mouse model of severe respiratory viral infection showed vagal sensory neuron mobilization of the alarmin HMGB1 (High Mobility Group Box protein 1) and provided evidence that HMGB1 can act on vagal sensory neurons via its cognate receptor RAGE (receptor for advanced glycation end-products) to induce neuronal firing and increased sprouting of neurites . This provides a potential mechanism for altered sensory neuron sensitivity and structure in pulmonary diseases and may suggest a previously unrecognized target for anti-HMGB1 therapy, currently being developed for use in patients.Airway sensory nerve plasticity may induce further respiratory pathology and morbidity. The state-of-the-art review by Drake and colleagues summarizes evidence that such plasticity occurs in asthma and chronic cough. Biopsy samples from both patient groups show increased nerve fiber density and changes in neurochemical phenotype, while advances in RNA sequencing, 3D microscopy and physiological assays are beginning to shed light on possible mechanisms involved and eventual functional implications . Sood et al. investigated deep breath-induced bronchodilation in patients with chronic cough versus patients with classic asthma, cough-variant asthma and healthy controls. Their surprising finding was that the deep inspiration index was significantly lower in cough with normal airway sensitivity versus individuals with either asthma or healthy controls, suggesting that the bronchodilating effect of deep inspiration is impaired in chronic cough without asthma . Bai et al. provided an overview of the perplexing problem of why women are more likely to develop chronic cough than men and disproportionately prone to poor quality of life resultant from cough. Evidence for mechanistic and sociological differences is presented, providing a strong interrogation of sex- and gender-differences in a common respiratory condition and highlighting the need for more research into this important clinical observation . Sykes and Morice reviewed the state of play in chronic cough and cough hypersensitivity clinical research, including the current pipeline of antitussives. They contrasted this with the topic of cough hyposensitivity, highlighting the ‘two faces’ of cough presented to clinicians and the challenge of developing effective antitussives that suppress unwanted coughing while preserving defensive cough needed to protect against aspiration (Sykes and Morice).Coughing is a critical defensive mechanism for keeping the airways clear from potentially dangerous inhaled, aspirated or locally produced substances. However, altered cough sensitivity leading to excessive coughing is a common, often-debilitating problem. Conversely, insufficient coughing predisposes to early death from aspiration pneumonia. Olsen et al. investigated the cough-suppressing actions of two centrally antitussive drugs (GABA agonist baclofen and opiate codeine) in cats. They showed that neither appears to suppress spinal circuits involved in chest wall and abdominal motor drive, but likely exert their antitussive effects via the brainstem (Defense of the pulmonary system is inarguably essential; however, more research is required to fully elucidate the mechanisms and consequences of pulmonary defensive processes. In submissions originating from four continents and reflecting the efforts of established experts and emerging researchers, this research topic describes the cutting-edge understanding of pulmonary defenses in health and disease. Readers are provided with insight into processes including cough hyper and hypo -sensitivity, sensory neural mechanisms, and sex differences in pulmonary defense, providing strong foundations for future inquiry.


There are two common hypotheses to explain such high comorbidity between nicotine dependence and schizophrenia (SZ): self-medication for decreasing psychiatric symptoms or common environmental risk factors can predispose to both nicotine dependence and other risky behaviors in SZLittle is known about the influence of cigarette smoking comorbidities such substance use disorder (SUD), criminal history, or risky decision among patients with SZ.The Iowa Gambling test (IGT) was administered to thirty-nine patients with SZ of whom 69% reporting cigarette smoking. Both groups were evaluated using a socio-demographic questionnaire and clinical assessment using PANSS and self-report questionnaire the Barratt Impulsiveness Scale (BIS-11). To evaluate decision making was evaluated with the Iowa Gambling Task (IGT).The full SZ sample performed worse on the IGT then normal population. Smokers with SZ performed significantly worse than nonsmokers on the IGT primarily because they preferred “disadvantageous” decks to a greater degree. The PANSS and impulsivity tendencies (BIS-11) did not predict overall performance on the IGT. Smokers with SZ had impaired affective decision-making. Behavior suggested preferential attention to the frequency amount of gain and inattention to amount of loss suggesting impairments in risk/reward decision-makingThis study is the first to compare IGT in smokers and nonsmokers with SZ with adjustment of SUD, criminal history, and existing tattoo to further examine IGT performance. These results support the hypothesis that comorbidities between nicotine dependence and SZ can be linked to other common factor that is associated with other externalizing behaviors in SZ.No significant relationships.


Certain percentage of the first-episode schizophrenia patients presents with negative symptoms, which persists over the year and influence treatment outcomes . Treatment of negative symptoms has been a significant continuous clinical challenge. Majority of recently published guidelines recommend antipsychotic monotherapy as the standard of care, recommending antipsychotic combination therapy only after a failed trial with clozapine . However, real-life forces clinicians to look for possible combinations of medications early on, especially to tackle negative symptoms. The systematic review of global prescribing practices covering four decades found the pooled median rate of antipsychotic combination therapy approximately 20% . One of the largest retrospective studies every conducted  assessed rehospitalisation rates and the long-term use of antipsychotic polypharmacy in schizophrenia. Antipsychotic combination treatment was associated with an approximate 10% lower relative risk of psychiatric rehospitalisation compared with antipsychotic monotherapy . Real-world effectiveness study of antipsychotic monotherapy vs. polypharmacy in schizophrenia from Eastern Europe is also supporting this approach . At the same time antipsychotic combination therapy can increase the total antipsychotic dose burden, frequency of adverse effects, potential drug-drug interactions and incur additional costs. In our recent naturalistic study in schizophrenia outpatients (n=120) with insufficient effectiveness of previous antipsychotics therapy on negative symptoms, we were able successfully switch therapy form several different antipsychotic combinations to monotherapy and gain clinical benefits .No significant relationships.


Sleep complaints and disorders are two of the most common disturbances to health and well-being in later life. This study examined how evening electronic media use and daytime sedentary behaviors affect subsequent sleep hours and perceived sleep quality, and whether consistent sleep hours  moderate these associations. Data were drawn from 241 older adults (Mage = 74.02) from the Daily Experiences and Well-being Study who completed ecological momentary assessments and wore an accelerometer for four days on average. A series of conditional fixed-effects models indicated that older adults reported more sleep disturbances on nights following the evening computer use. Sedentary behaviors and evening television viewing were not associated with sleep quantity and quality. Older adults with more consistent hours of bedtime reported better sleep quality regardless of their evening electronic media use and daytime sedentary behaviors, thereby highlighting the importance of sleep regularity in later life.


Background: Diversion of resources from infection prevention activities, personal protective equipment supply shortages, conservation (extended use and reuse) or overuse with multiple gown and glove layers, and antimicrobial prescribing changes during the COVID-19 pandemic might increase healthcare-associated infection (HAI) incidence and antimicrobial resistance. We compared the incidences of Clostridioides difficile infection (CDI), methicillin-resistant Staphyloccocus aureus bloodstream infection (MRSA BSI), and vancomycin-resistant enterococci bloodstream infection (VRE BSI) reported by California hospitals during the COVID-19 pandemic with incidence data collected prior to the pandemic. Methods: Using data reported by hospitals to the California Department of Health via the NHSN, we compared incidences in the second and third quarters of 2020 (pandemic) to the second and third quarters of 2019 (before the pandemic). For CDI and MRSA BSI, we compared the standardized infection ratios , and we calculated the P values. No adjustment model is available for VRE BSI; thus, we measured incidence via crude incidence rates . We calculated incidence rate ratio (IRR) with 95% CI for VRE BSI. To examine the possible effect of missing data during the pandemic, we performed a sensitivity analysis by excluding all facilities that had incomplete data reporting at any time during either analysis period. Results: Incidence measures and numbers of facilities contributing data in prepandemic and pandemic periods are shown in Table P = .05 for either MRSA BSI or CDI between the prepandemic and pandemic periods . Crude VRE BSI incidence increased during the pandemic compared to the prepandemic period . Excluding facilities with incomplete data had minimal effect. Conclusions: We found insufficient evidence that MRSA BSI or CDI incidence changed in California hospitals during the pandemic relative to the prepandemic period; however, there was a significant increase in the crude incidence of VRE BSI. Next, we will include interrupted time series analyses to assess departure from long-term trends, including a risk-adjusted model for VRE BSI. Additionally, we will evaluate for changes in central-line–associated bloodstream infection incidence and antimicrobial resistance among HAI pathogens.Funding: NoDisclosures: None


Using 2018 Medicare data, we examined the relationship between dual eligibility and injury-related emergency department use among a cohort of assisted living residents . We fit multilevel models with random intercepts at the assisted living community and license type levels. The baseline rate of injury-related emergency department emergency department use was 0.17. After controlling for resident characteristics , license type characteristics , and assisted living community characteristics , being dually eligible for Medicare and Medicaid was associated with a 12% increase in the probability of having an injury-related emergency department visit . Assisted living communities that serve duals may have fewer resources and staff to provide personal care, potentially leading to increased rates of injuries.


Immunotherapy for allergy has been practiced for over 100 years. Low-dose repeated exposure to specific allergen extracts over several months to years can successfully induce clinical tolerance in patients with allergy to insect venoms, pollen, house dust mite, and domestic animals. Different regimens and routes for immunotherapy include subcutaneous, sublingual, oral, and intralymphatic. Food allergies have been difficult to treat in this way due to high anaphylactic potential and only recently the first immunotherapy for peanut allergy has received regulatory approval. Several clinical trials have indicated high efficacy in desensitisation of peanut-allergic individuals using oral immunotherapy, which allows for safer administration of relatively high allergen concentrations. Still, the risk of adverse events including serious allergic reactions and high anxiety levels for patients remains, demonstrating the need for further optimisation of treatment protocols. Here we discuss the design and outcomes of recent clinical trials with traditional oral immunotherapy, and consider alternative protocols and formulations for safer and more effective oral treatment strategies for peanut allergy. Arachis hypogaea) is an immunoglobulin E (IgE)-mediated hypersensitivity, which tends to develop early in life and is typically lifelong with resolution in only 20% of affected children ..13].4 and IgA and initial increase followed by a decrease in serum food-specific IgE . Th. ThLactoesponses , 40, andThe long-term follow-up study PPOIT2 published in 2017  aimed toAnother Australian interventional study (ACTRN12617000914369)  will assIn addition to whole peanut protein preparations and adjunctive therapeutics, alternative allergen forms for immunotherapy are being researched and trialled to overcome the associated adverse events of exposing the gastrointestinal tract to whole allergenic protein. DNA vaccines and peptide therapeutics are under investigation for other routes of administration and could be considered for OIT. Hypoallergenic preparations also offer an alternative. These interventions potentially could decrease treatment duration, the need for strict medical supervision and may lead to higher patient adherence.A novel immunotherapeutic approach utilises intradermal administration of plasmid DNA encoding peanut allergens and is currently being tested for safety, tolerability, and immune response in a Phase 1 trial (NCT03755713)  in 20 paVaccination with plasmid DNA will need further proof against apprehensions about the safety of this vaccine type, categorised as gene therapy. Issues have been raised due to the hypothetical risk of integration of the vaccine itself into the genome or long-term persistence of the administered plasmid DNA that could lead to triggering the production of anti-DNA antibodies . These aOther vaccination approaches are currently undergoing pre-clinical testing in animal studies. A study performed by Storni et al. used peanut-sensitised mice to demonstrate a protective effect of vaccination with extracts of roasted peanut or the single allergens Ara h 1 or Ara h 2 coupled to immunologically optimised Cucumber Mosaic Virus-derived virus-like particles (CuMVtt) . ModifieThe alteration of allergenic protein structure and function influences immunoreactivity and allergenicity . Amongstin vitro basophil reactivity to PVX108, providing further support for an improved safety profile of PVX108 over whole allergen immunotherapies [An alternative approach to prevent IgE-mediated adverse events is to utilise T-cell reactive peptide fragments of the allergen that are not recognised by antibodies . Australherapies .OIT enables the administration of much higher doses of allergen with greater safety than other routes of administration of AIT. The recently approved peanut OIT product PALFORZIA represents a promising treatment option for peanut-allergic patients to increase the threshold of clinical tolerance for protection from accidental ingestion and possibly achieving sustained unresponsiveness. Clinical data collection of healthcare providers in the REMS program will help ongoing research in assessing the effectiveness of PALFORZIA in the real-world setting and guide future clinical trial design for OIT.This and other new strategies to enhance the safety and efficacy of immunotherapy for peanut allergy are currently under clinical exploration. Promising trends amongst different protocols and methods to improve OIT success with decreased adverse events are to alter OIT protocols regarding timing and dosing: a lower allergen delivery dose and a slow, delayed escalation rate in OIT treatment seem approachable in the near future.Adjunctive therapy with biologics in parallel to OIT protocols may help to mitigate risk and improve tolerability, especially in highly allergic individuals. Many trials using the biologic Omalizumab as adjunctive treatment in OIT have shown a raised threshold tolerance dose of OIT treatment, thereby reducing the risk of severe adverse reactions. Other biologics such as Abatacept are not optimal for extended use, which limits their application in OIT protocols. Dietary supplements such as probiotics have been shown to improve treatment tolerability with decreased adverse effects over longer periods of time, presenting a cost-effective adjunct treatment with OIT.Alternative formulations that circumvent exposure of the gastrointestinal tract to IgE-reactive, whole allergenic proteins, such as peptides, DNA vaccines, and other hypoallergenic preparations, could present a safer, more cost-effective approach for OIT for peanut-allergic individuals.More studies are needed to fully elucidate the best protocol to achieve sustained unresponsiveness. Most current clinical trials include objective laboratory biomarker analysis in patients undergoing OIT protocols . The rap


Gos is a declarative Python library designed to create interactive multiscale visualizations of genomics and epigenomics data. It provides a consistent and simple interface to the flexible Gosling visualization grammar. Gos hides technical complexities involved with configuring web-based genome browsers and integrates seamlessly within computational notebooks environments to enable new interactive analysis workflows.https://github.com/gosling-lang/gos), and documentation with examples can be found at https://gosling-lang.github.io/gos.Gos is released under the MIT License and available on the Python Package Index (PyPI). The source code is publicly available on GitHub ( Existing genomic visualization tools are tailored towards specific tasks and as such are limited in terms of expressiveness .clinvar.ipynb notebook contains a custom visualization to view human genetic variants from the ClinVar database (We provide a set of Jupyter notebooks (doi: 10.5281/zenodo.7321052) demonstrating how genomics visualizations may be created, combined and controlled with Gos. The getting-started.ipynb and navigation.ipynb notebooks introduce a basic concepts of the Gosling grammar through the declarative Python API, with sections detailing data-binding, creation of custom Tracks and Views  and programmatic viewer navigation. The data-loading.ipynb notebook displays an identical visualization for a dataset hosted remotely, on the local filesystem, as well as a Pandas DataFrame, demonstrating the versatile data capabilities of our library.The Gos is a Python library for authoring interactive genomics visualizations via the Gosling grammar. Instead of editing deeply nested and repeated JSON data structures, users write simple Python programs which emit valid Gosling JSON specifications. Python scripts may therefore be repurposed to accommodate new data sources, offering a convenient utility to produce custom visualizations as a part of traditional bioinformatics pipelines.Beyond this core functionality, Gos provides a unified framework to iteratively visualize genome-mapped data within interactive computational notebooks. Responsive genomics visualizations are woven between code and prose, and optional utilities host local and in-memory datasets without requiring users to exit the analysis environment or save intermediate results to disk. Gos connects flexible web-based genomics visualization with the larger scientific Python ecosystem, and we anticipate this integration can foster the use of numerical and machine learning libraries to actualize higher-level genomics visualization tools such as recommendation systems (


Dear Editor,Airway protection and maintaining patency during neurosurgical cases requiring prone positioning, is of paramount importance. Due to complexity of procedure , it becomes difficult to manipulate an airway once the surgery commences: With provision of video laryngoscopes (VDL) it becomes easier to identify airway edema and other related abnormalities.


The bi-directional relationship between mental and physical illness is well established. Therefore, in order to lower the already high mortality rates associated with psychiatric disorders, physical health issues must be closely monitored in this population . A recent Lancet commission highlights emerging strategies and recommendations for improvement of physical health outcomes in patients with chronic mental disorders. These strategies involve better integration of physical and mental health care, combined with broader implementation of lifestyle interventions to reduce elevated cardiometabolic risk and attenuate medication side-effects [3].To assess psychiatrists’ confidence levels in physical healthcare competencies; to explore whether confidence was related to learning opportunities.Physical healthcare learning objectives were extracted from the Irish College of Psychiatrists’ training curriculum. An electronic questionnaire was sent to 50 psychiatrists in one Irish healthcare region with a catchment area of c. 450,000. Participants had to rate confidence levels for each competency on a five-point Likert scale and the availability of learning opportunities for attaining each competency.66% response rate was achieved. A majority reported confidence in cardiovascular examination, interpreting blood results and evaluating comorbidities. A minority reported confidence in interpreting imaging, electrocardiograms and recognising medical emergencies. This corresponds to a relative paucity of learning opportunities.Clinical implication Programmes for trainee doctors and CME opportunities for consultant psychiatrists would benefit from an emphasis on physical health examination and modules on interpreting investigations and the recognition of medical emergencies.


Airborne aerosols reduce surface solar radiation through light scattering and absorption , influence regional meteorology, and further affect atmospheric chemical reactions and aerosol concentrations. The inhibition of turbulence and the strengthened atmospheric stability induced by ADEs increases surface primary aerosol concentration, but the pathway of ADE impacts on secondary aerosol is still unclear. In this study, the online coupled meteorological and chemistry model  with integrated process analysis was applied to explore how ADEs affect secondary aerosol formation through changes in atmospheric dynamics and photolysis processes. The meteorological condition and air quality in the Jing-Jin-Ji area  in January and July 2013 were simulated to represent winter and summer conditions, respectively. Our results show that ADEs through the photolysis pathway inhibit sulfate formation during winter in the JJJ region and promote sulfate formation in July. The differences are attributed to the alteration of effective actinic flux affected by single-scattering albedo (SSA). ADEs through the dynamics pathway act as an equally or even more important route compared with the photolysis pathway in affecting secondary aerosol concentration in both summer and winter. ADEs through dynamics traps formed sulfate within the planetary boundary layer (PBL) which increases sulfate concentration in winter. Meanwhile, the impact of ADEs through dynamics is mainly reflected in the increase of gaseous-precursor concentrations within the PBL which enhances secondary aerosol formation in summer. For nitrate, reduced upward transport of precursors restrains the formation at high altitude and eventually lowers the nitrate concentration within the PBL in winter, while such weakened vertical transport of precursors increases nitrate concentration within the PBL in summer, since nitrate is mainly formed near the surface ground. They pe3) concentration. Atmospheric aerosols cause significant attenuation of ultraviolet radiation and affect photolysis rates and species chemical cycles   . In 2013nditions . The airnditions . But und22.5 concentration is shown in The overall modeling methodology for the study is detailed previously in Following our previous analyses , three sTo further explore these impacts, process analysis (PA) technology  was appl3−2 in January and July, respectively. Decreased solar radiation weakens surface turbulence and reduces the daily maximum PBL height. The perturbation of ADEs on solar radiation and the PBL is presented in To provide insight into how ADEs affect sulfate concentration, the vertical distribution of sulfate concentration and related process responses to ADEs is presented in 2 concentration and sulfate formation. Compared with winter, ADED changes sulfate by promoting sulfate formation in July , resulting in weakened nitrate formation at around 900 m in winter. Conversely, the transport direction of nitrate is bottom up in July. Therefore, restrained upward transport of NOx increases the formation of nitrate in the near-surface layer.The ADE impacts on nitrate are then investigated. The vertical profile of nitrate affected by ADEs is presented in The vertical distribution of the nitrate IPR response to ADEs is presented in 42.5 and its components. (2) ADEs through the photolysis pathway inhibit sulfate formation during winter in the JJJ region and promote sulfate formation in July. The differences are attributed to the alteration of effective actinic flux affected by aerosol optical depth (AOD), solar zenith angle, and SSA. (3) ADEs through the dynamics pathway act as an equally or even more important route compared with the photolysis pathway in affecting secondary aerosol concentration in both summer and winter. (4) ADEs through dynamics traps formed sulfate within the PBL, which increases sulfate concentration in winter. Meanwhile, the impact of ADEs through dynamics is mainly reflected in the increase of gaseous-precursor concentrations within the PBL, which enhances secondary aerosol formation in summer. (5) Reduced upward transport of precursors restrains the formation of nitrate at high altitude and eventually lowers the nitrate concentration within the PBL in winter, while such weakened vertical transport of precursors increases nitrate concentration within the PBL in summer, since nitrate is mainly formed near the surface ground.In addition to directly deteriorating air quality, aerosol diminishes solar radiation due to light scattering and absorption, thereby influencing regional meteorology and further modulating air quality. The impact of ADEs on secondary aerosol is more complicated than primary aerosol. This study quantified the impacts of ADEs on secondary inorganic aerosol using the two-way online coupled meteorology and atmospheric chemistry model (WRF–CMAQ) with integrated process analysis. The main pathways through which ADEs affect aerosol concentrations were examined. The key conclusions are the following. (1) ADEs reduce solar radiation and decreases PBL height, concentrating aerosol in the near-ground layers. In this analysis, ADEs improved the model performance for simulating PMSupplement1


The normal decline in skeletal muscle mass that occurs with aging is exacerbated in patients with chronic obstructive pulmonary disease (COPD) and contributes to poor health outcomes, including a greater risk of death. There has been controversy about the causes of this exacerbated muscle atrophy, with considerable debate about the degree to which it reflects the very sedentary nature of COPD patients vs. being precipitated by various aspects of the COPD pathophysiology and its most frequent proximate cause, long-term smoking. Consistent with the latter view, recent evidence suggests that exacerbated aging muscle loss with COPD is likely initiated by decades of smoking-induced stress on the neuromuscular junction that predisposes patients to premature failure of muscle reinnervation capacity, accompanied by various alterations in mitochondrial function. Superimposed upon this are various aspects of COPD pathophysiology, such as hypercapnia, hypoxia, and inflammation, that can also contribute to muscle atrophy. This review will summarize the available knowledge concerning the mechanisms contributing to exacerbated aging muscle affect in COPD, consider the potential role of comorbidities using the specific example of chronic kidney disease, and identify emerging molecular mechanisms of muscle impairment, including mitochondrial permeability transition as a mechanism of muscle atrophy, and chronic activation of the aryl hydrocarbon receptor in driving COPD muscle pathophysiology. Chronic obstructive pulmonary disease (COPD) patients are often affected by more severe limb skeletal muscle atrophy than is typical of normal aging , with moIn addition to skeletal muscle atrophy, there are many other manifestations of adverse limb muscle impact in COPD  . It is iTo further test for manifestations of mitochondrial dysfunction in COPD limb muscle, in one of our prior studies we used a histochemical diagnostic approach to identify muscle fibers with severe mitochondrial respiratory capacity impairment and observed a markedly elevated abundance of muscle fibers exhibiting depletion of mitochondrial complex IV activity but relatively normal (or elevated) mitochondrial complex II activity in vastus lateralis muscle biopsies of COPD patients . This phIt is noteworthy that muscle fibers with complex IV deficiency typically exhibit a compensatory upregulation of mitochondrial biogenesis and mtDNA copy number in a futile attempt to restore the bioenergetic capacity of the muscle fiber (futile because the high burden of mutated mtDNA templates precludes biogenesis of properly functioning mitochondria). Whereas in age-matched control subjects fibers with complex IV deficiency and normal or elevated complex II activity (Cox-/SDH+) exhibited greater than 2-fold higher levels of mtDNA copy number compared to normal muscle fibers (Cox+/SDH+), this was not seen in COPD patient muscle  and thisFurther to the relevance of specific mitochondrial enzymatic abnormalities in COPD, a recent study using a mouse model of pulmonary emphysema observed a down-regulation of subunit c of complex II (SDH) that was associated with lower muscle respiratory capacity and greater muscle fatigability. In addition, genetic gain of function experiments to rescue complex II in mice with emphysema improved muscle respiratory capacity and reduced fatigability . Amongstvia actin cleavage , and inflammation, amongst others. These consequences are further compromised during acute exacerbations of disease severity, which can occur secondary to bacterial or viral infections . As a re2 supply through modulation of bioenergetic stress . Their results showed that hypoxia further exacerbated both the decline of muscle mass and shift towards type IIx fibers seen with bed rest  exposure in the etiology of COPD muscle impairment, there is growing evidence that long-term cigarette smoking plays a key role in initiating the muscle impairments with COPD (as summarized in in vitro recapitulates the muscle atrophy (The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with a wide variety of endogenous and exogenous ligands that leads to increased transcription of detoxifying pathways, including cytochrome P450 enzymes such as Cyp1A1  Figure , above.  atrophy  and mito atrophy . Finally atrophy  , and the histone H2A variant gamma-H2AX (γH2AX). These senescence markers were recently evaluated in the context of aging human skeletal muscle using immunolabeling of muscle cross-sections from young (18–35 years) vs. old (>70 years) subjects. The authors noted that despite using numerous commercially available antibodies for each senescence marker, γH2AX was the only one detectable in human muscle, and strikingly it did not evidence an increase with aging and instead was elevated exclusively in myonuclei of obese vs. lean subjects . KeepingAnother biomarker of aging that has received some attention in the context of COPD skeletal muscle impairment is the anti-aging hormone α-klotho (hereafter referred to as klotho). Klotho serves as a co-receptor for fibroblast growth factor 23 to activate a variety of fibroblast growth factor receptors throughout the body , and is Skeletal muscle of COPD patients is characterized by an exacerbated degree of atrophy relative to age-matched healthy subjects. They also exhibit other manifestations of skeletal muscle impairment, including exacerbated fatigue, weakness, a fast fiber shift, mitochondrial dysfunction, and an accumulation of denervated muscle fibers that is associated with a failed reinnervation transcriptional profile. Notably, COPD patient skeletal muscle exhibits evidence of an increased frequency of mitochondrial permeability transition events, where recent evidence identifies mitochondrial permeability transition as a mechanism of muscle atrophy operating through mitochondrial ROS and caspase 3. There are likely multiple contributing factors underlying the skeletal muscle alterations in COPD, including chronic TS exposure, systemic hypoxia, systemic hypercapnia, and inflammation. Notably, smoking mouse models show that chronic TS exposure without overt lung disease can cause muscle atrophy, mitochondrial impairment, and neuromuscular junction alterations, underscoring the likely role of long-term TS exposure in initiating the muscle impairment in COPD. Furthermore, recent evidence suggests that chronic activation of the AHR in skeletal muscle is likely to play an important role in driving these TS-induced muscle alterations as constitutive activation of the AHR without TS exposure recapitulates many of the same muscle phenotypes induced by chronic TS exposure. In addition to TS-mediated AHR activation, the higher circulating level of the tryptophan metabolite kynurenine seen in COPD patients, which is likely a consequence of impaired renal function, can also activate the AHR. This suggests multiple pathological insults involved in COPD may converge upon the AHR in causing skeletal muscle toxicity. Although an exacerbated accumulation of senescent cells in COPD muscle seems unlikely to underlie the exacerbation of aging muscle phenotypes , reduced circulating levels of the longevity-promoting klotho protein have been reported in COPD and some evidence suggests this may contribute to the adverse muscle phenotypes. In conclusion, COPD patient skeletal muscle alterations are likely to be driven by a combination of factors, some of which precede COPD disease diagnosis , and others that are part of the COPD patient’s systemic milieu  and disease comorbidities . Based upon emerging evidence, preclinical models examining the potential of approaches targeting the mitochondrion  and the aryl hydrocarbon receptor may be valuable in seeking new targeted therapies for treating and preventing adverse skeletal muscle impact in COPD patients.