People with substance use disorder are at risk of complications of drug use and frequent hospitalization and may continue to use substances during admission to acute care. Acute care harm reduction strategies including oral or injectable prescription opioids may aid in care retention and improve health outcomes in this patient population.A 58-year-old woman with refractory opioid use disorder was admitted to hospital for management of dysphagia secondary to esophageal stricture. She received injectable opioid agonist therapy using a continuous ambulatory drug delivery (CADD) pump in order to facilitate completion of her hospital admission.The patient successfully received acute medical care with the use of a CADD pump for consistent, patient-controlled opioid administration, with the support of an interdisciplinary team and by respecting the patient’s own substance use goals. Harm reduction is a patient centered, evidence-based approach compromising one aspect of care for people with substance use disorder (SUD) . Harm reIn Canada, harm reduction services such as distribution of sterile equipment, safe disposal of used equipment, supervised consumption services and distribution of overdose prevention kits are readily utilized in the community setting and not widely implemented in inpatient settings . The impA CADD pump contains a reservoir of medication, typically a parenteral opioid such as morphine, hydromorphone or fentanyl, and can be programmed to administer an automated hourly infusion of medication through an intravenous or subcutaneous line. The pump can also deliver patient-initiated bolus doses at pre-programmed time intervals, with a lockout period to prevent inadvertent toxicity. CADD pumps are typically reserved for the management of acute pain in the post-operative period, or for management of chronic malignant pain or dyspnea in patients with life-limiting diagnoses. Utilizing a CADD pump for the purposes of reducing harm by providing a safer opioid supply was uncharted territory for our team.A 58-year-old woman with a 30-year history of infection with human immunodeficiency virus (HIV) was admitted to hospital for management of dysphagia secondary to esophageal stricture. The patient was diagnosed with a squamous cell carcinoma of the oropharynx 2 years prior and received treatment with an extended course of radiation therapy. She remained free of cancer recurrence but developed esophageal stricture as a late complication of radiation therapy. Her past medical history was complex; in addition to HIV infection, she was known to have HIV-induced immune thrombocytopenic purpura, hepatitis C infection, chronic obstructive pulmonary disease, depression, recurrent facial cellulitis, and polysubstance use including opioid use disorder. Her esophageal stricture resulted in progressive dysphagia, and she was eventually unable to swallow any tablets including her anti-retroviral therapy.She had been using injection drugs for several decades, including heroin, crack cocaine, and fentanyl. She was prescribed slow-release oral morphine (SROM) (60 mg three times a day) and immediate release oral morphine (10 mg four times a day) by her community addiction specialist as opioid agonist therapy (OAT). As the patient’s dysphagia progressed, she began to crush, heat, and inject her prescribed opioids. At the time of admission to hospital she also reported using crack cocaine 10–12 times per month.Historically, the patient preferred to receive medical management in the outpatient setting. When hospital admission was required, she would often leave before treatment completion against medical recommendations. During previous hospitalizations, the patient experienced stigma surrounding her substance use and expressed frustration with practitioners who under dosed or delayed the administration of opioids because of her substance use history, thereby prompting patient-directed discharge.The patient presented to her outpatient HIV clinic dehydrated and cachectic secondary to severe dysphagia. Her facial cellulitis caused periorbital edema resulting in extremely limited vision; despite this she was injecting her prescribed morphine with varied success. Outpatient care options had been exhausted and she required an urgent hospital admission for lifesaving therapies. In order to engage the patient with inpatient care, the team proposed a CADD pump to deliver opioids at a dose equivalent to her community prescription, and to offer the option of patient-controlled breakthrough dosing thus returning control to the patient. She agreed to present to the emergency department, with the hope that a CADD pump would alleviate the constant need to advocate for OAT in acute care.The patient was forthcoming about her opioid use and transparent about her plan to continue using opioids in the community. The team recognized that enforcing abstinence or OAT with buprenorphine-naloxone or methadone would deter her from engaging with care. Increasing SROM was not an option because of her severe dysphagia, and hospital policy restricted the delivery of IV opioids on the unit thus removing the option of injectable (intravenous) hydromorphone. Instead, a shared decision was made to modify risk through subcutaneous opioid agonist therapy delivered through a continuous ambulatory drug delivery (CADD) pump. A CADD pump provided her with the autonomy to self-administer breakthrough doses without having to rely on staff.The patient’s home morphine dose was converted to the parenteral equivalent, which proved challenging as the precise bioavailability of sustained release oral morphine when injected is unknown. Further, because of her impaired vision, her degree of success in injecting her opioids in the days prior to admission was questionable, thus her true opioid requirements were not clear. During the initial period in the emergency department, the patient was started on intermittent subcutaneous hydromorphone as a bridge until she transferred to the medical unit and could be initiated on a CADD pump. see Table Despite having a team committed to providing harm reduction, on Day 3 of admission the patient experienced withdrawal symptoms and it became evident that her baseline opioid coverage was insufficient. Over the subsequent two days, the patient was assessed multiple times per day and her CADD dosing was uptitrated to prevent withdrawal and cravings. On Day 5 of admission, she underwent gastroscopy with dilatation of her esophageal strictures. The subsequent day, she was cleared by the speech language pathologist to resume oral intake. The hourly rate on the CADD pump was stopped and she was able to resume her home dose of SROM by mouth. She continued the CADD for bolus dosing of morphine until she was medically stable for transfer to a transitional facility for ongoing supportive care. She remained stable on her home dose of SROM during transition care.Over the subsequent months, the patient’s esophageal strictures recurred, and she required readmission on several occasions to optimize nutrition and for eventual feeding gastrostomy tube insertion and tracheostomy. Her opioid use disorder was managed with the CADD pump on each presentation. With every admission, she was more willing to engage with the healthcare system with the knowledge that she would receive effective treatment with reduced fear of discrimination and stigmatization.Written informed consent from the patient, Katherine McNeil, was obtained to report her case in the medical literature. Katherine specifically requested use of her real name. Katherine was a brave and generous woman with goals and dreams, despite facing tremendous challenges and tragedy. The months she spent in the hospital were difficult and working closely on the manuscript with the authors provided her a sense of hope and purpose.We describe a case of a woman with severe opioid use disorder who received injectable opioid agonist therapy using a continuous ambulatory drug delivery (CADD) pump in order to facilitate completion of a hospital admission. This unconventional harm reduction strategy was borne out of the requirement to support a patient in need of medical intervention but with continued use of substances.This approach succeeded in engaging the patient in care for several reasons. Firstly, in acute care we were well-positioned to conduct routine assessments for any withdrawal or oversedation symptoms (using continuous oximetry). In the past, when the patient displayed irritability and frustration toward staff, this was dismissed as the ‘drug-seeking behavior of a challenging patient.’ We recognized the behavior as a coping mechanism in a patient experiencing withdrawal, and the symptoms were mitigated with regular monitoring and rapid uptitration of injectable OAT (iOAT) via the CADD pump. Notably, this is a resource-intensive process that requires appropriate training of staff; however, by taking advantage of the controlled, high-resourced environment in the acute care setting optimal patient care was delivered.The patient was also supported by an interdisciplinary approach to her care. She had a history of negative interactions with the medical establishment and often felt misunderstood and judged in hospital settings. Her long-standing nurse practitioner from the HIV clinic advocated daily for her care needs. Marginalized or ‘challenging’ patients benefit when they have an advocate who can remind the team of their humanity. Addiction and palliative care specialists collaborated to manage the CADD pump and advocated to use a CADD pump as a novel approach to accessing iOAT in hospital. The team’s social worker facilitated the transition to a step-down hospital that could support the patient’s goals of care. Her community addiction specialist was in close communication with the hospital team to ensure a seamless discharge back to community-based care.Most critically, the medical team placed the patient’s own goals at the center of her care plan. The primary goal of her admission was for definitive management of her dysphagia; she did not voice a desire for drug rehabilitation or abstinence and it is crucial that patients are not faced with an ultimatum in order to receive essential health care services. Individuals with opioid use disorder face stigma in hospital, and this is further exacerbated by punitive responses from a medical establishment that perpetuate power imbalances for marginalized patients. The CADD pump was successful in part because it returned a degree of control to the patient, thereby empowering her to achieve her individualized treatment goal.Admittedly, there are potential barriers and obstacles to using a CADD pump for harm reduction purposes. Although it provides a safer opioid supply and allows the patient control over breakthrough doses, it can be time consuming for staff particularly during the initial stage of titrating and monitoring. However, once a therapeutic dose is established, nurses no longer need to provide regular breakthrough doses thereby significantly reducing. The additional cost and physical resource of having CADD pumps available could prohibit uptake of CADD pumps for harm reduction purposes. Lastly, there is expertise and knowledge required in prescribing and programming a CADD pump.The patient successfully received acute medical care with the use of a CADD pump for consistent, patient-controlled opioid administration, with the support of team-based collaborative care and by respecting the patient’s goals. To replicate this success and establish a strong foundation for harm reduction interventions, we advocate for system-level changes including mandatory educational programs to enable de-stigmatizing care, as well as the creation of harm reduction committees to identify champions within healthcare institutions to spearhead evidence-based, non-coercive policies for people with SUD in acute care. Formal policy change, educational and accreditation requirements will help to create hospitals that are safe for all people to make healthy choices based on their individual needs.


Objective: The objective of this case report is to highlight the importance of patent foramen ovale (PFO) as a potential cause of central retinal artery occlusion (CRAO). Methods: A teenage girl presented with a sudden painless onset of vision loss in the right eye, which was accompanied by frontal headaches and vertigo. The patient was referred to the Ophthalmology Department, where subsequent examination revealed a best corrected visual acuity of 20/ 400 and a positive relative afferent pupillary defect (RAPD) in the right eye. Fundoscopy and optical coherence tomography confirmed the diagnosis of central retinal artery occlusion following which investigations to rule out hematologic, vascular, and cardiac causes were performed.Results: Transoesophageal echocardiography revealed PFO as the cause of this cryptogenic stroke. All the necessary blood testing work was performed . Transoesophageal echocardiography revealed right to left shunt. Conclusions: This case along with other reported evidence in literature support the strong connection between PFO and CRAO. Closure of symptomatic PFO may result in prevention of severe visual loss. Abbreviations: CRAO = central retinal artery occlusion, PFO = patent foramen ovale, RAPD = relative afferent pupillary defect, BCVA = best corrected visual acuity, OCT = Optical coherence tomography, IOP = Intraocular pressures, TTE = transthoracic echocardiography, HM = hand motion, TEE = transesophageal echocardiogram  As CRAO affects the inner retinal layers , it has devastating functional consequences in the form of severe visual impairment. Unfortunately, current medical science has no definite treatment protocol to reverse the ischemic effects of CRAO. This is unlike stroke, in which treatment protocols are well established [2]. Etiologies for CRAO vary with the age groups and persisting risk factors but often, it is associated with rare conditions as well. One such rare emerging association is patent foramen ovale (PFO). It is a benign condition (25% of population), in which embryologic interatrial communication persists even after the neonatal year, which can lead to right to left sided shunt. In utero, PFO allows right to left shunt, but soon after birth and with establishment of pulmonary circulation, the PFO closes due to a drop in pulmonary pressure and an increase in left atrial pressure as compared to the right. Thus, a persistent PFO, can rarely be responsible for embolic episodes resulting in stroke and CRAO [3-5]. Other published cases have also reported other ocular problems including branch retinal artery occlusion and optic neuropathy to be associated with PFO, which has also been reported as a causative factor, leading to migraine and decompression sickness in deep sea divers [6].Sudden unilateral loss of vision is an ophthalmic emergency and central retinal artery occlusion (CRAO) is one of the leading important causes. It is analogous to acute stroke of the eye and has an incidence of 1 in 100,000 people . PFO has been found in 20-25% of adults and recent evidence has suggested a positive correlation between right to left shunt mediated by PFO and risk of stroke and migraine [8]. Wieder et al. reported a similar case of PFO with right to left shunt and CRAO. They also conducted a review of literature and found seven such other cases, in which PFO has been implicated as a causative factor of CRAO. In their review, they cited transesophageal echocardiogram (TEE) as being more sensitive in diagnosing PFO as compared to TTE . Our case also reported a similar occurrence of CRAO and PFO.PFO has been reported in a few case reports, in which the patients presented with sudden acute loss of vision attributed to CRAO or BRAO. These reports did not find any additional risk factors for CRAO and have mostly reported such cases in young adults [11].Similarly, Zhu et al. described a case of a 46-year-old male with history of amaurosis fugax in one eye for 20 minutes followed by acute painless and profound loss of vision. The patient did not have any other risk factors of CRAO apart from PFO documented on TEE and blood split-flow from right to left atrium when performing Valsalva breath during the Foaming test [12]. Historically, the time interval between complete CRAO and irreversible retinal ischemia has been found to be 90-240 minutes and all efforts shall be done to dissolve or dislodge the thrombus. However, recent literature quotes the window period between occlusion to infarction to be 12-15 minutes. This is the reason there is so strong evidence of efficacy of any intervention in case of CRAO [13].Retinal artery occlusion is a visually devastating condition, in which acute obstruction of central retinal artery leads to irreversible ischemia of the retinal ganglion cells [14]. Similarly, a case by Zhu et al., in which PFO acted as a source of paradoxical emboli in presence of internal carotid hypoplasia and resulted in CRAO, was recently reported [11]. Similarly, PFO has also been associated with branch retinal artery occlusion, which is a relatively visually forgiving event, but the pathogenesis is the same . The causal relationship between PFO and thromboembolism has not been fully established and all proposed mechanisms are complex. These include emboli forming in atrial septum, transient arrythmias leading to thrombus formation and paradoxical emboli from peripheral venous system. This is the reason a thorough cardiologic examination shall be performed in case a calcific embolus is detected in retinal circulation and TEE is more sensitive in detecting PFO as compared to TTE [14].PFO can be compounded with other pathologies when associated with CRAO. This includes a case, in which atrial septal aneurysm associated with PFO resulted in CRAO in a young adult [With this interesting case report, we conclude that PFO shall be considered in cases of CRAO and branch retinal vein occlusion (BRAO) in young patients, in which no other risk factors can be identified. It is imperative to refer these patients to the cardiology team so that necessary intervention can take place to prevent future thromboembolic events. This case report also highlights the merit of elective treatment of PFO in asymptomatic patients.Conflict of Interest StatementThe authors state no conflict of interest.Informed Consent and Human and Animal Rights statementInformed consent has been obtained from the parents of the patient included in the study.Authorization for the use of human subjectsEthical approval: The procedures followed were in accordance with the ethical standards of the institutional committee on human experimentation of The Aga Khan University Hospital, Karachi, Pakistan and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.AcknowledgementsNone. Sources of FundingNone. DisclosuresNone.ContributionAll authors contributed equally to this article.


Chen J-Q. et al.; Chen X-M. et al.; Chen Y. et al.; Choudhury et al.; Deng et al.; Du et al.; Geng et al.; He et al.; Huang, Liu et al.; Huang, Zhang et al.; Ke et al.; Kong et al.; Li et al.; Li and Gong; Ma et al.; Yu et al.; Zhao et al.). A variety of biomarkers are used, including standard diagnostic tests, imaging, proteomics and genomics to classify and study subsets of disease with novel methodologies. The clinical topics vary from oncology to pulmonary disease, dermatology, and traumatic brain injury. A variety of patient-specific biomarkers are highlighted, including genetic profiles, RNA signatures and routine serum assays that may be used to more precisely classify individual patients and predict their long term outcomes or therapeutic response. The broad range of highly specialized conditions covered on this topic is expansive yet demonstrates the critical roles of open access publication in data sharing, translation of data science methods across disciplines, and real-world data to drive future improvements in patient outcomes.The publication of this open-access Research Topic on innovative approaches to and aspects of precision medicine across a diverse set of clinical conditions underscores the recent evolution and ethical considerations of translational research in medicine. The Research Topic includes 17 distinct articles on data science methods across a diverse range of conditions to discern the impact of baseline patient characteristics, medical decision-making and specific therapeutic interventions on outcomes  as the pinnacle, yet multiple alternative pathways exist; however, they are less valued. RCTs are overly obsessed with data collection, with paradoxical paucity of details on data quality or validity, such as independent adjudication of imaging measures by a core lab or related methodology. Post-marketing surveillance of most therapeutic drugs or devices is largely non-existent in most geographies around the world, including the United States. Registries and vehicles to evaluate quality of healthcare delivery are largely unfunded, unregulated, and devoid of validated data checks or measures to assess generalizability in routine clinical practice across most geographical regions.Perhaps such gaps in translational research could be excused in prior years, yet the abundance of patient-specific information in the current big data era should prompt a reconsideration of traditional research paradigms. The big data era has not only sparked interest in large, diverse datasets, as it has also heralded the emergence of big data analytics, including artificial intelligence methods that can be readily deployed with current clinical data. In the United States, The Health Insurance Portability and Accountability Act of 1996 (HIPAA) was intended to promote data sharing and interoperability of clinical data systems, rather than to solely ensure individual patient privacy. Unfortunately, HIPAA has been cited to restrict data sharing rather than the original purpose of portability and dissemination of data and related findings. Data sharing at the National Institutes of Health and other platforms is a now a top priority. In routine care, the electronic health record systems, individual hospitals, institutions, provider groups, and academicians limit data sharing due to competition with others and the relative strength in controlling or restricting such data access. The marked expansion of knowledge with artificial intelligence is almost unbelievable with recent advances such as ChatGPT and likely future development of related medical applications, yet access to data is a starting point. Medical or clinical data has already been simplified and codified by common data elements or variables that exist in most medical specialties, laboratory assays and medical imaging modalities. Simultaneously, data scientists know of such potential yet lack the clinical expertise to apply such analytical techniques to specialized clinical topics. Unsupervised machine learning or artificial intelligence will likely always depend on periodic retraining by expert annotations or clinical guidance, yet patterns may rapidly emerge from machine learning that human efforts would take generations to realize. Unlike recent concerns over false ground truths inadvertently used to train machine learning, most medical data relate to timed, quantitative measures of biological significance such as physiological measures , laboratory values, imaging, and increasing use of functional outcome measures that are widely available.These changes sparked by the big data era and continued practice of imprecise medicine pose an ethical conundrum regarding current clinical research methodology and the responsibility of various parties. Academicians often initiate, design and perpetuate clinical research constructs such as trial design, the nature of clinical trials, statistical measures employed, and many entrenched traditional approaches, yet there is no concrete imperative to innovate such methodology. Industry partners are often seen as biased in trying to accelerate innovation of products, yet they need clinical research data not just leading up to RCTs, but afterwards in routine clinical practice. Regulatory bodies revert to predicate methods without clear imperative to facilitate advances, with a much larger concern for patent safety, far before efficacy. Yet once approved, most therapies go largely unmonitored in the general population. Fortunately, regulatory bodies are now implementing diversity requirements in prospective clinical trials. Routine healthcare providers remain relatively passive, as they can only use established methods or approved products. The most responsible and ethical approach for all would start with dissemination of data to collaboratively mine and discern potentially subtle yet pivotal insights on how precision medicine of individual patient response to a specific therapy is practiced on a daily basis around the world.st century.Open access publications, as in this Research Topic, and collaborative data sharing are critical in the big data era and further advances in precision medicine. This selective example of research articles provides an example to demonstrate such progress toward a broader swath of specific medical disciplines or specialties to be covered in future years. There is undoubtedly an indirect yield or benefit of disruptive innovation that may emerge from applying such novel methodologies or even medical therapies such as drugs or devices to other medical conditions. Open access is a critical barrier to overcome disparities in low income countries, to encourage collaboration and to promote data sharing as the initial steps in our transformation from imprecise medicine to precision medicine of the 21DL conceived the design and content of this editorial manuscript, drafted, revised, and approved the submitted version.


The COVID-19 pandemic has had a profound impact on the lives of many individuals globally. Older adults, specifically, were deemed more susceptible to the infection and its consequences when compared to their younger counterparts. The lockdown disrupted their daily routines, overwhelmed hospitals made it difficult to access timely healthcare services, the economic recession resulted in financial loss, mass quarantine led to separation from family members, and limited internet access and lack of smartphones posed difficulties in using digital technologies  were able to emotionally cope with the negative stressors brought on by the pandemic. In fact, these individuals exhibited a reduction in negative emotional states during the remission period as compared to the outbreak period, indicating their ability to manage the pandemic-related stressors. These studies suggest that older adults' resilience and experience with challenging life events have helped them develop effective coping strategies to better manage stressors during the pandemic (Lind et al., Despite high vulnerability to the COVID-19 infection, older adults report higher resilience and better psychological adjustment compared to their younger counterparts during the pandemic. In particular, older age is related to less anxiety and depression (Bruine de Bruin, Jiang and Carstensen found that older adults preferred to interact with emotionally close social partners over novel social partners both during the peak of the pandemic and after vaccines had become available. Serrao Hill et al. found that having a close social partner contributed to higher levels of subjective wellbeing among older adults. These findings suggest that a close partner can promote older adults' wellbeing, even in a stressful situation. Conversely, according to Panes Lundmark et al. low social network satisfaction emerged as a key predictor of persistent loneliness among older adults both prior to and during the pandemic. Of note, Sams et al. found that a substantial 83% of older adults were concerned about the disruption of their social activities as a consequence of the social restrictions implemented during the COVID-19 pandemic. Overall, the findings of these studies highlight the importance of supporting older adults in maintaining meaningful social engagement as a mean of managing stressful situations, including those associated with the pandemic.The presence of social support networks seems also to contribute to older adults' emotional wellbeing during the pandemic (Cavallini et al., Panes Lundmark et al. revealed that, although cognitive impairment did not emerge as significant risk factor for situational and persistent loneliness, cognitive impairment was more frequent within individuals living in persistent loneliness than individuals that did not experience loneliness. Conversely, Fu et al. did not reveal an influence of participants' behavioral and emotional coping skills on cognition. Sutton et al. examined whether poorer psychological and physical wellbeing was associated with worries about cognitive functioning and concerns about developing dementia in older adults during the COVID-19 pandemic. These authors revealed that 25.1% of participants reported concerns about their cognitive health, and that these worries were significantly related not only to poorer psychological wellbeing but also to worse physical conditions in terms of fatigue and poorer sleep quality and quality of life.Considering that in older adults there is a natural decline in cognitive functioning, it is conceivable to hypothesize that long period of quarantine may indirectly lead to feelings of reduced cognitive efficiency due to disruptions in daily routines (Fiorenzato et al., Almonds et al. observed that 71% of participants had a pre-existing sleep disorder, and certain conditions worsened during the pandemic, notably insomnia in women and obstructive sleep apnea in men. Individuals with primary education displayed higher sleep latency in comparison to those with a Ph.D., indicating an influence of educational level on sleep latency. In addition, disturbances in sleep were correlated with symptoms of depression, anxiety, and irritability in older individuals. It is plausible to suggest that during a difficult period, such as the COVID-19 pandemic, the practice of social distancing and isolation may further intensify existing sleep problems and psychological distress in the older population, ultimately resulting in more adverse health status outcomes (Lebrasseur et al., It is worth pointing out that both subjective cognitive decline (Tsapanou et al., In summary, the articles included in this Research Topic provided us with valuable insights into the consequences of the COVID-19 pandemic on the overall wellbeing of older adults, and also offered potential strategies to enhance the physical and mental wellbeing of the aging population in the aftermath of catastrophic events such as the COVID-19 pandemic.IB: Writing—original draft, Writing—review & editing. TL: Writing—original draft, Writing—review & editing. GM: Writing—original draft, Writing—review & editing. AR: Writing—original draft, Writing—review & editing.


Heart failure with preserved ejection fraction (HFpEF) accounts for around half of all cases of heart failure and may become the dominant type of heart failure in the near future. Unlike HF with reduced ejection fraction there are few evidence-based treatment strategies available. There is a significant unmet need for new strategies to improve clinical outcomes in HFpEF patients. Inflammation is widely thought to play a key role in HFpEF pathophysiology and may represent a viable treatment target. In this review focusing predominantly on clinical studies, we will summarise the role of inflammation in HFpEF and discuss potential therapeutic strategies targeting inflammation. Heart failure with preserved ejection fraction (HFpEF) accounts for half of all cases of Heart Failure. Broadly speaking, it is defined as symptoms and signs of HF in the presence of a left ventricular ejection fraction (LVEF) of more than 50%, usually in the presence of a cardiac structural or functional abnormality such as left ventricular hypertrophy, left atrial enlargement or diastolic dysfunction . At leasDespite intense research interest in HFpEF, there are few evidence-based treatment options. Randomized trials targeting neurohormonal and sympathetic nervous system using angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs) and beta blockers, which provide clear benefits in HF with reduced ejection fraction  (HFrEF),A recent breakthrough has been the positive outcome trials using sodium-glucose cotransporter 2 (SGLT2) inhibitors in HFpEF. EMPEROR-Preserved  and DELIOne of the key reasons for our inability to develop successful HFpEF treatments is its pathophysiological complexity and our limited understanding of this. This even extends to our definition of HFpEF. The textbook definition of HFpEF as a form of diastolic dysfunction leading to impaired left ventricular filling and reduced cardiac output does not fully capture the complexity of HFpEF. Various definitions of HFpEF have been used in guidelines and for inclusion in clinical trials with different profiles of patients consequently included under the HFpEF umbrella . DetaileHFpEF involves a complex interplay between comorbidities such as hypertension, diabetes mellitus, renal failure, COPD, obesity and atrial fibrillation and cardiac structural and functional abnormalities such as LV hypertrophy, myocardial fibrosis, myocardial stiffness, endothelial dysfunction and oxidative stress . DiffereThe cardiometabolic phenotype has been most concisely identified across various HFpEF cohorts. Patients with this phenotype usually have a higher prevalence of comorbidities such as hypertension, obesity, diabetes and insulin resistance and are usually 10–15 years younger  than patRecently, the term “metainflammation” has been used to describe the association between metabolic stress caused by conditions such as diabetes, obesity, insulin resistance and non-alcoholic fatty liver disease and chronic inflammation . This chRegardless of the underlying phenotype, what has been consistently identified throughout these studies is that inflammation is highly prevalent in HFpEF and is associated with worse symptoms and prognosis . Over haAs well inflammation being upregulated in HFpEF compared to HFrEF, inflammation is also associated with worse cardiac structural and functional abnormalities in HFpEF patients. A recent proteomic study of 228 HFpEF patients studied 47 proteins involved in inflammatory pathways and found that systemic inflammation was associated with an increased number of comorbidities, diastolic dysfunction and right ventricular dysfunction. Inflammation was also upregulated compared to controls . This waUpregulation of inflammation in HFpEF not only leads to worse cardiac structure and function but is also associated with worse prognosis, demonstrated using various inflammatory biomarkers. Several studies have reported an independent association between elevated C-reactive protein and increased risk of death or HF hospitalisation in HFpEF patients, including after adjustment for natriuretic peptide levels , 31–33. In summary, there is an abundance of evidence  suggesting that inflammation could play a key role in the pathophysiology and clinical outcomes of HFpEF.The innate immune system has been proposed as a key mediator of inflammation in heart failure. Oxidative stress and hypertension cause the recruitment of inflammatory leukocytes, the most notably being neutrophils which is the most abundant leukocytes in circulation. In response to endothelial cells damaged by systemic inflammation, neutrophils secrete MPO. MPO also reduces NO availability . Both ofIn the context of the innate immune system, inflammasomes are also activated by tissue damage. The Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome is the best described inflammasome relating to the heart . NLRP3 iWhen tissue is damaged, molecules such as adenosine triphosphate, angiotensin II, fatty acids and glucose are released. The presence of these molecules activates NLRP3 in a 2-step manner . In the Although much research has been focused on the innate immune system in HF, there is increasing recognition of the role of the adaptive immune system in HF pathophysiology. It is hypothesised that the adaptive immune system may play and important role in the remodeling process in response to chronic myocardial injury , 45. EndThere is a large amount of evidence suggesting the role obesity and metabolic stress play in the inflammatory state of HFpEF, particularly relating to inflammation-dependent oxidative and nitrosative stress –56. The With the burgeoning observational evidence and mechanistic studies supporting the role of inflammation in HFpEF, there has been intense interest in clinical trials of anti-inflammatory therapies in HFpEF. In this section we will summarise previously tested and potential future strategies targeting inflammation in HFpEF.The renin-angiotensin-aldosterone system (RAAS) is central in the development of heart failure . When thUnlike in HFrEF however, RAAS blockade in HFpEF does not improve clinical outcomes to anywhere near the same extent . In the Beta-blockers reverse the neurohormonal effects of the sympathetic nervous system, improving symptoms and outcomes in HFrEF , 74. BetThe evidence for beta-blockers in HFpEF is weaker however  though tSodium-Glucose co-Transporter 2 (SGLT2) Inhibitors have recently become an established part of HF care, following their initial development as type 2 diabetes treatments. They act by blocking SGLT2, a protein in the kidney that promotes the reabsorption of glomerular filtrated glucose back into the systemic circulation, contributing to about 90% of glucose reabsorption , causingThe mechanisms of benefit of SGLT2 inhibitors in HF are still unclear and are a subject of intense ongoing research interest –86. SGLTExercise Training can be a potential means of reducing systemic inflammation. Reduced exercise capacity is a significant part of the problem in patients with HFpEF, leading to reduced quality of life and worse prognosis . The curRegular exercise helps to exert antioxidant and anti-inflammatory effects by targeting the cardiovascular system, adipose tissues and immune system . Upon muFew clinical studies have as yet evaluated the effects of exercise training on markers of inflammation. It is possible that systemic inflammation may also modify the effects of exercise in HFrEF . There aMethotrexate is an anti-inflammatory commonly used in conditions such as rheumatoid arthritis (RA). Methotrexate use was associated with a reduction in cardiovascular events in patients with rheumatological conditions . A recenThere have been no specific trials of methotrexate in HFpEF as yet. In the CIRT   is a heme containing peroxidase that is expressed mainly in neutrophils. They play a role in the development of acute and chronic vascular inflammation which is proposed as an underlying mechanism in the development of HFpEF . In the There remain few evidence-based treatment options for HFpEF and there is an urgent need for novel therapeutic strategies. As described in There is a plethora of observational and trial evidence supporting the role of inflammation as an important part of the pathophysiology of HF. Although the CANTOS trial showed the merit of an anti-inflammatory approach in cardiovascular disease, most other trials of anti-inflammatory therapy in HF have been neutral at best, though these have predominantly been in HFrEF. Very few clinical trials of anti-inflammatory strategies have been conducted in HFpEF populations however, and it is possible that inflammation may play a differential role in HFpEF to HFrEF. It may also be that patients could be selected for trials based on baseline levels of inflammation—those with higher levels of systemic inflammation might be more likely to benefit from anti-inflammatory therapy. Such a strategy needs to be refined as there are many potential inflammatory markers that could be used however we do not know which might translate to clinical benefit. The most widely-used is high-sensitivity C-reactive protein—in the CANTOS trial patients were eligible if their hsCRP level was ≥2 mg/l . Optimal


To paraphrase Charles Dickens, today “it is the best of times, it is the worst of times” for cancer drugs. Great progress in cancer therapy has been made thanks to the combined impact of better supportive care, ever improving drugs and earlier cancer detection. On the other hand, the Anthropocene era brings new challenges due to increased human impact of environmental factors, which along with changes in diet and lifestyle may contribute to a worrisome increase in early-onset cancers, a situation viewed as a potential emerging global epidemic [The “war on cancer”  began wiepidemic .Conventional chemotherapy, one of the oldest anticancer weapons brought in late 1940s, encompasses alkylating agents, antimetabolites, natural products, hormones and steroids. Chemotherapy relies on the concept of eliminating the fast growing cancer cells [Targeted therapies that emerged in the late 1980s are based on the assumption that cancer cells express and rely on the use of various unique targets for their survival. A success story of a targeted BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) spurred development of other targeted therapies, many of which effectively eradicated human cancers in animal models but failed to show clinical efficacy. Immunotherapy with monoclonal antibodies is a variation on the theme of targeted therapy. In particular, immune-checkpoint inhibitors do not kill cancer cells directly but instead mobilize the immune system to do the killing. In some cases, high success rates have been noted even in metastatic cancer  but subsTargeted gene editing using CRISPR  with the bacterial RNA-guided CRISPR-Cas9 system has opened a new chapter in the drug development . SeveralFuture cancer drug development might focus on a hybrid warfare that explores combinations of the old and new drugs for possible synergies, examines schedule and dose dependence of the treatments, and surveys individual proteomes and microbiomes for their potential as drug targets. The growth may be supplemented by combining and mining big data emerging from the laboratory and clinical research, and health records in various formats ranging from medical imaging to data from wearables and medical devices .One can expect that artificial intelligence (AI) will play some role in the future drug development. A canary in the mine has already been spotted as the world’s first anti-fibrotic small molecule inhibitor discovered and designed using generative AI is being tested in the Phase II clinical trial .Rewording Dr. Strangelove, does it mean that we must learn how to stop worrying and love the AI? Not necessarily so. The term AI could be a misnomer since we do not yet know what is actually the natural intelligence . The lim


Although we have sent humans into space for more than 50 years crucial questions regarding kidney physiology, volume regulation and osmoregulation remain unanswered. The complex interactions between the renin-angiotensin-aldosterone system, the sympathetic nervous system, osmoregulatory responses, glomerular function, tubular function, and environmental factors such as sodium and water intake, motion sickness and ambient temperature make it difficult to establish the exact effect of microgravity and the subsequent fluid shifts and muscle mass loss on these parameters. Unfortunately, not all responses to actual microgravity can be reproduced with head-down tilt bed rest studies, which complicates research on Earth. Better understanding of the effects of microgravity on kidney function, volume regulation and osmoregulation are needed with the advent of long-term deep space missions and planetary surface explorations during which orthostatic intolerance complaints or kidney stone formation can be life-threatening for astronauts. Galactic cosmic radiation may be a new threat to kidney function. In this review, we summarise and highlight the current understandings of the effects of microgravity on kidney function, volume regulation and osmoregulation and discuss knowledge gaps that future studies should address. Fluid redistribution from the legs to the abdomen, thorax and the head was one of the first observations that was considered to impact kidney physiology2. Many studies during space flight and simulated microgravity on Earth have tried to establish the effects of microgravity on kidney function and volume homeostasis. However, essential questions remain unanswered.The effect of microgravity on kidney function and volume homeostasis has been of interest for researchers since 1966Investigation of kidney physiology in space is complex because of the simultaneous changes in osmoregulation, volume regulation and glomerular and tubular function in response to microgravity. To understand the exact impact of microgravity, all responses should be thoroughly tested. This goal is difficult to achieve due to logistic issues and the fact that most measurements are influenced by fluid and nutrient intake, countermeasures, and space flight duration.3. More targeted countermeasures that are directed to intervene in kidney physiology and volume homeostasis could conceivably ameliorate orthostatic intolerance. The problem of orthostatic intolerance will become even more important during future exploration missions when astronauts are exposed to longer periods of microgravity and then get re-exposed to a hypogravity environment upon landing on a planetary surface without the usual medical care that is available after return to Earth4. In these situations, an orthostatic intolerance-induced fall could be life- and mission threatening. In addition, kidney stone formation could jeopardize future long-term deep space missions where evacuations times will be significantly longer than currently from the International Space Station. In this review, we discuss the key findings of the last decades of relevant research and highlight the most important research gaps concerning volume regulation, osmoregulation and kidney function that should be addressed to prepare astronauts and space medicine experts for future deep space exploration missions  is subject to change. Most studies investigating extracellular volume have reported an initial and persistent reduction without restoration of extracellular volume to pre-existent values, but data on the skin compartment, which represents an important part of the extracellular volume, are scarce30. The exact contribution of both interventions to the mitigation of orthostatic hypotension and potential restoration of the nonosmotic sodium storage capacity is unknown.Muscle sodium storage capacity may be restored by countermeasures that are directed to prevent muscle atrophy. This hypothesis is supported by recent studies demonstrating that the combination of exercise training during space travel and saline loading right after space travel is able to mitigate orthostatic related symptoms32. High cortisol levels are generally known to impact protein and muscle catabolism but the recently discovered role in infradian sodium excretion rhythms is less known10. Although cortisol can bind to the mineralocorticoid receptors, thus promoting sodium retention, long-term balance studies associated high cortisol levels with a negative sodium balance33. Future studies are needed to investigate the interaction between cortisol, (muscle) catabolism and long-term volume and osmoregulation during space flight.Considering the recently proposed role of cortisol in sodium homeostasis, one could hypothesize that the hypothalamic-pituitary-adrenal axis could contribute to volume regulation during microgravity. Throughout the relatively short Skylab flights, cortisol levels were increased but long-duration space flights showed that cortisol levels return to baseline values after 160 days34. Like on Earth, a high sodium diet or sodium infusion are able to decrease aldosterone levels indicating that sodium balance remains linked to the renin-angiotensin-aldosterone system (RAAS)35. Nevertheless, RAAS hormones are not always in line with the net sodium balance, in particular as observed during early space flight when a positive sodium balance was observed and aldosterone levels were low to normal6.The renin-angiotensin-aldosterone system has been studied many times during space flight with different results. These conflicting data can, at least in part, be explained by differences in assays, body posture and space flight duration. Overall, renin and aldosterone levels sharply decrease on the first day of space flight and seem to return to or above pre-flight values thereafter25. Mid-regional pro-atrial natriuretic peptide responded similarly to an increase in sodium intake from 2 to 5.5 grams/day in space and on Earth, however, measurements were reset to lower levels in space25. This finding may be partly explained by the reduction in thoracic blood volume during space flight25. So far it is unknown whether the reduction in natriuretic peptides is an appropriate physiological response to reduced cardiac preload or whether the response is maladaptive such that sodium balance gets out of tune.Natriuretic peptides also fall right after space flight but, in contrast to RAAS hormones, remain significantly suppressed after four weeks in space36. Several studies demonstrated that plasma and urine catecholamine levels do not change during long-term space flight38. On the other hand, measurements of whole-body noradrenaline spill-over and peroneal nerve muscle sympathetic activity in six male astronauts during a shorter term space shuttle mission indicated increased sympathetic activity39. Possibly, sympathetic measurements during shorter term missions may be confounded by the psychological and physiological stresses imposed by adaptation to the space environment combined with an intense work schedule. Likewise, data after return to Earth show variable sympathetic responses. Although two studies observed a sharp increase in sympathetic activity, a third study could not reproduce this finding despite a substantial increase in cardiac output and decrease in blood pressure40. However, the link between orthostatic intolerance and sympathetic nerve activity is supported by studies that relate orthostatic complaints to an attenuated increase in plasma norepinephrine and increased norepinephrine metabolites after space flight, and increased plasma norepinephrine after bed rest42. Interestingly, plasma norepinephrine levels were not affected by acute saline infusion suggesting that a change in volume status may not be the sole mechanism affecting sympathetic nervous activity during spaceflight35. Given the importance of the sympathetic nervous system in maintaining orthostatic tolerance and the intense cross-talk between sympathetic nervous system and the RAAS system, which is reviewed in the following section, there is a need for additional studies on sympathetic responses during long duration missions.Data on sympathetic nervous activity during space flight are contrasting and may be related to mission duration as well as inter-individual variability in the susceptibility to the space environment43. Both sympathetic activation and RAAS activation may lead to sodium retention, and contribute to the variability in blood pressure responses during space flight44. However, only two studies with ten subjects on three different space flights investigated the interaction between neurohumoral systems and sodium and water balance  fluid losses and is associated with high skin sodium content.Another determinant of water balance is skin water loss. In contrast to what would be expected in hypobaric conditions, transepidermal water loss is reduced during space flight by approximately 10–20%56. This approach resulted in subjects drinking and urinating more and more every day, from approximately 1100 ml/day to 2400 ml/day at the end of the study. These data suggest that there is a second source of water, which may be of metabolic origin due to muscle wasting, and that the reduced fluid intake may be a consequence. Another study investigated an oral water load of 600 mL during short- and long-term space flight and bed rest. Unexpectedly, urinary flow rate did not increase in space whereas a 5-fold increase was observed on Earth after acute supine position, short-term or long-term bed rest57. The observations in space suggest dehydration at baseline resulting in water retention but measurements of urine output and osmolality, after an overnight fast, were similar to the bed rest groups and did not indicate dehydration. This study underscores the lack of understanding of the water balance during microgravity and the notion that data from bed rest studies can be significantly different from data during actual space flight58.Data from studies with fluid intake interventions may help to understand the physiology of water balance. Sato et al. conducted a 20-day study of head-down tilt bed rest and instructed participants to drink the amount of fluid that was excreted by the kidneys the previous day48. As plasma osmolality does not change after long-term space flight, the increased levels may be the consequences of decreased plasma and extracellular volume. Grigoriev et al. showed that the antidiuretic effect of ADH may be attenuated as a result of spaceflight, by demonstrating that higher ADH levels were needed to achieve a similar reabsorption rate of osmotically free water48. An important limitation, however, is that measurements were performed directly post-flight, after restoration of gravity. Other post-flight measurements show that the urine concentrating ability of the kidney after a 12-hour food and water deprivation test decreases with space flight to a maximum urine osmolality of 782 mOsm/L after 3–6 months of space flight, which could also be explained by a limited capacity to increase the tonicity of the renal medulla.Water balance is mainly regulated by antidiuretic hormone (ADH), which is secreted upon high plasma osmolality or decreased extracellular volume. During long-term space flight, ADH levels are increased57. However, the limited decrease in urine osmolality after water loading during space flight suggests either increased ADH levels or changes in the responsiveness of renal collecting ducts to ADH57. This discrepancy between space flight and bed rest may be explained by the observations that, in contrast to the increased ADH levels during space flight, ADH decreased during bed rest60.In the previously discussed water loading study of Norsk et al., which demonstrated an attenuated increase in urinary flow rate after water loading during space flight compared to bed rest, ADH was not measured6. Surprisingly, this increase took place during the initial reduction in extracellular and plasma volume, and reduced fluid intake, although the latter has been demonstrated to increase glomerular filtration rate on Earth61. Another remarkable observation is that creatinine clearance, which is known to overestimate glomerular function, was lower than measured inulin clearance. The observed reduction in plasma urea concentration supports the temporary increase in glomerular filtration rate6.Reports on the effects of space flight on glomerular function vary. Leach et al., who measured creatinine and inulin clearance simultaneously during space flight, reported an increase during the first days and normalization to baseline values afterwardsThe transient increase in (estimated) glomerular filtration rate has not been observed in older studies, which can be explained by the lack of in-flight measurements and the absence of instructions to maintain adequate fluid intake in these studies.6. This finding cannot explain the previously discussed observation of sodium retention, which may therefore be of tubular origin. On the other hand, the large standard deviation of effective renal plasma flow should be taken into account. The coefficient of variation of day-8 creatinine clearance and effective renal plasma flow in the study of Leach et al. was 27% and 39%, respectively, whereas the percentage change from baseline was 20% and 17%, respectively6. This suggests that the low sample size and the relative inaccuracy of effective renal plasma flow measurements may contribute to the previously suggested difference in both variables. An alternative explanation is that space conditions led to a change in the balance between afferent and efferent arteriolar constriction in renal glomeruli thereby increasing filtration fraction.The observed increased glomerular filtration rate by Leach et al. was not associated with a significant increase in effective renal plasma flow, which suggests an increase in filtration fraction62. As 24-hour creatinine excretion did not change this indicates an increase in creatinine clearance in the first 2–3 weeks after bed rest. Interestingly, cystatine C levels showed a similar decrease as plasma creatinine. Contrary to space flight observations, plasma urea increased during the first weeks of bed rest and was related to the observed reduction in muscle mass62. Interestingly, Arinell et al. found different results in females63. After 60 days of bed rest, plasma cystatin C showed a significant increase whereas creatinine levels remained stable. These data underline the importance that future studies should take sex-specific effects into account.During bed rest, in healthy men, plasma creatinine levels gradually decreased to a new steady state after 2–3 weeks reflecting loss of muscle mass64. One could expect that such changes would translate into proteinuria, impaired urine acidification, altered urine electrolyte content or a diminished renal concentrating ability.Histopathological assessment of rat kidneys after simulated microgravity demonstrate degeneration and necrosis of tubular epithelial cells67.The most notable change in 24-hour urine composition during space flight is the increase in urine calcium excretion, which is attributed to increased bone mineral loss. Daily urine calcium excretion has been reported to increase by approximately 20–80 mg/day during microgravity and bed rest70. The amount of water loss due to hypercalciuria is likely to be clinically relevant. In hypercalciuric children, hypercalciuria was associated with a 250-mL higher 24-hour urine volume and a 147-mOsm/kg lower urine osmolality70. Administration of synthetic ADH (DDAVP) in these hypercalciuric children increased urine osmolality, but only to the baseline levels of normocalciuric children. In bed rest studies, a decrease in aquaporin-2 excretion was associated with increased calcium excretion supporting the view that urinary calcium can modulate ADH-dependent urine concentration through down-regulation of aquaporin-2 expression/trafficking68. This phenomenon could have a key role in the prevention of urine supersaturation and stone formation due to hypercalciuria and may contribute to the uncoupling of sodium and water balance during space flight.Hypercalciuria has been linked to water balance as high urine calcium content has been demonstrated to induce renal water loss by proteolysis of aquaporin-2 and thereby limiting the maximal urinary concentration and calcium saturation71. One of these proteins, aminopeptidase A, is a marker of renal tissue hypoxia and tubular dysfunction. However, aminopeptidase A was only found seven days after space flight and was not observed three days after return to Earth. Given the lack of in-flight measurements, this may therefore represent changes after space flight instead of changes induced by space flight. Future studies investigating the effects of tubular function during microgravity should therefore focus on in-flight measurements.Pastushkova et al. analysed urine protein composition before and after space flight. Three proteins, which were not found in the urine on Earth, could be detected in the urine after space flight67. Among 357 astronauts, 22 experienced at least one episode of kidney stones with a total of 36 episodes72. Kidney stone formation is of mission critical significance. In the past, one Soviet in-flight renal stone episode nearly caused a mission termination due to intractable symptoms, but was relieved by spontaneous stone passage by the cosmonaut just before an urgent deorbit was initiated73. It has been demonstrated that space flight associated changes in urinary biochemistry favour kidney stone formation75. Besides hypercalciuria due to bone mineral loss, hyperphosphaturia, hypocitraturia and a decrease in urine pH have been reported following microgravity67. These changes are the consequence of the high dietary acid load whereas phosphate is also from bone origin76. In addition, the reduced water intake and diuresis is a major risk factor for kidney stones. Interestingly, microgravity may also have a direct effect on the crystallisation and nucleation of nascent kidney stones, but this is dwarfed by the net biochemical urinary changes observed in space flight77. Changes in the microarchitecture of the kidney can lead to abnormal renal calcification and stones (e.g. in medullary sponge kidney), and changes in the nephron architecture can occur with the kinds of electrolyte disturbance that can be caused by space flight79.Astronauts and cosmonauts have an unusually high rate of kidney stone formation, despite being screened for absence of kidney stone history. Stones are usually seen after space flight65. For this reason, potassium-citrate is routinely used by crewmembers who are felt to be at elevated risk for stone formation. During bed rest, potassium-magnesium-citrate supplements were demonstrated to attenuate the increase in calcium excretion and increase in urine pH, potassium, magnesium and citrate levels66. Besides these supplementations, compliance with the daily recommended fluid intake of >2 litre is crucial to lower the risk for renal stone formation. Other dietary recommendation such as a low protein and sodium diet, which are advised to individuals at risk for renal stones on Earth, are thought to have a similar beneficial effect during space flight but hard data to support these recommendations are lacking. Considering the previously discussed knowledge gaps on sodium and water homeostasis and muscle metabolism, the exact net effect of these general recommendations may turn out differently.A randomized, double-blind, placebo-controlled study that was performed during space flight demonstrated that supplementation of potassium-citrate lowers urinary calcium excretion and increases urine citrate levels and urine pH during space flight thus reducing the propensity to cristallization80. These large effects, however, could not be reproduced during space flight26. A more recent study demonstrated that the combination of alendronate and advanced resistive exercise device training could lower daily calcium excretion below pre-flight values and prevent an increase in calcium oxalate and calcium phosphate relative supersaturation, an effect that could not be achieved with exercise only81. In the last decades, vitamin D supplementation was initiated during space flight and doses were increased to 1000 IU per day, which was demonstrated to keep vitamin D at adequate levels without any adverse effects82. However, the exact relation between vitamin D dose, 24-hour calcium excretion and renal stone risk during space flights remains to be defined.By interfering with bone resorption, the renal excretion of calcium may also be limited. Administration of pamidronate was shown to reduce 24-hour calcium excretion with 55–65% during the first 30 days of bed rest whereas resistive exercise training was not effective85. In fact, the kidney is the dose limiting organ in abdominal radiotherapy and total body irradiation83. Beside mitochondrial damage due to the oxidative stress generated by gravitational changes, GCR can further enhance mitochondrial damage through the radiation-induced reactive oxygen species86. The resulting mitochondrial damage affect the kidneys at multiple levels in both tubular and glomerular integrity, and micro- and macrovascular function88. To this date, data are limited, but there is emerging animal and astronaut data that link exposure to high atomic number and energy (HZE) ions to mitochondrial damage90. We postulate that the most vulnerable component of the kidney architecture is the proximal tubule, because of its high oxidative metabolism (mitochondria rich), its low glycolytic ability and its crucial role in mass transport of solutes and water. Indeed, tubular injury is an early and prominent histological feature in iatrogenic radiation nephropathy91. Due to their full dependence on mitochondrial aerobic metabolism, proximal tubular cells are extremely vulnerable to mitochondrial damage. Altogether, our understanding on the molecular and cellular mechanisms linked to how chronic exposure to GCR impacts kidneys remains to be elucidate and warrant urgent investigation to develop mitigation strategies.There is concern regarding the effect of galactic cosmic radiation (GCR) exposure on the longer missions planned as part of the Artemis Program and the Deep Space Transport/Mars Missions. To date this has mostly focused on the risk of carcinogenesis but the kidney is an exquisitely radiation sensitive organ92. To date, around 80 different drugs are available on the ISS93. Yet, only the pharmacokinetics of acetaminophen, scopolamine, promethazine and antipyrine have been tested in space94. Although, these studies have several limitations, an apparent trend toward altered drug disposition during spaceflight compared to measurements on Earth could be seen94. In particular, the expression changes of CYP450 superfamily of enzymes, which metabolizes 70–80% of all prescription drugs, was observed in rodents, but data in humans are lacking95. Drugs acting on the kidney might be useful for prevention of lithiasis and bone loss. For instance, thiazide-like compounds decrease calciuria, lower the incidence of recurrent kidney stones, prevent bone loss and appear to prevent hip fractures, but their use is limited by the lack of knowledge about their pharmacodynamics and kinetics during spaceflight97. Better understanding of renal changes and their influence on blood detoxification is a call for interdisciplinary programs.The kidney is not only an essential organ for fluid and ions homeostasis, it is also the main excretion pathway for xenobiotics, among them drugs and toxic compounds. Systematic pharmacodynamic and pharmacokinetic studies in space are lacking. Yet, the profound change in renal physiology could conceivably affect renal drug elimination. Moreover, anecdotal evidence suggests that the response to drug therapies may be altered in space. This issue coupled with limited shelf life of many medications and potential degradation through radiation might be particularly problematic during long-term lunar or mars missions where it is not possible to return to Earth on short noticeTo be able to safely increase the length of future space missions, we need future studies to investigate basic kidney physiology, osmoregulation and volume regulation, and develop new countermeasures that are directed to preserve kidney function and prevent potential life-threatening orthostatic complaints and kidney stone formation. A substantial part of these data could be gathered in studies that investigate other hypotheses but allow accurate documentation of sodium and water balance, and repeated urine collections and blood draws for relatively simple analyses of RAAS and antidiuretic hormones, natriuretic peptides, sympathetic nervous activity and catabolic hormones.


Infants’ first-person experiences are crucial to early cognitive and neural development. To a vast extent, these early experiences involve play, which in infancy takes the form of object exploration. While at the behavioral level infant play has been studied both using specific tasks and in naturalistic scenarios, the neural correlates of object exploration have largely been studied in highly controlled task settings. These neuroimaging studies did not tap into the complexities of everyday play and what makes object exploration so important for development. Here, we review selected infant neuroimaging studies, spanning from typical, highly controlled screen-based studies on object perception to more naturalistic designs and argue for the importance of studying the neural correlates of key behaviors such as object exploration and language comprehension in naturalistic settings. We suggest that the advances in technology and analytic approaches allow measuring the infant brain at play with the use of functional near-infrared spectroscopy (fNIRS). Naturalistic fNIRS studies offer a new and exciting avenue to studying infant neurocognitive development in a way that will draw us away from our laboratory constructs and into an infant’s everyday experiences that support their development. Infants’ first-person experiences are crucial to early cognitive and neural development. To a vast extent, these early experiences involve play, which in infancy takes the form of object exploration. Across the world, infants engage with objects every day , and singing. Naturalistic fNIRS studies using the free play paradigm will record neural responses to all of these experiences and behaviors and, therefore, will give us a window into the complexities of infant first-person experiences. Future studies will be able to look into the influence of labeling on infants’ brain responses to object exploration, how different types of object exploration  influence neural engagement as well as how these behaviors and their neural correlates vary across different socio-cultural contexts. Finally, naturalistic fNIRS studies offer a new and exciting avenue to studying infant neurocognitive development in a way that will draw us away from our laboratory constructs and into an infant’s everyday experiences that support their development.


Autism spectrum disorder (ASD) is associated with marked heterogeneity with respect to the development of executive function abilities. The bilingual advantage refers to the observation that individuals who speak two languages perform better on executive function tasks than monolinguals under some circumstances. There is not yet consensus, however, as to whether this advantage can be reliably demonstrated, nor is there consensus regarding under which conditions it emerges. Bilingual and monolingual children with ASD have comparable developmental outcomes, particularly in the areas of core ASD symptoms, cognitive function, and language. Still, despite the potential advantages that bilingualism may confer, clinicians commonly advise against providing a bilingual environment for children with ASD. The purpose of the present review is to provide an up-to-date assessment of the limited literature on bilingualism in children with ASD in order to inform evidence-based practice. Studies suggest a potential bilingual advantage in ASD in the areas of nonverbal intelligence quotient, adaptive functioning, and expressive vocabulary. A limited yet growing literature provides preliminary evidence for enhanced executive function ability in some children with ASD. Taken together, current evidence suggests that although a bilingual advantage may not be universally present in typical development, it may manifest under specific circumstances, conferring advantage for populations in which executive function is compromised. Further work is needed to develop consistent, evidence-based guidelines around language recommendations for families of children with ASD and to better understand the cognitive and brain mechanisms giving rise to the bilingual advantage in clinical developmental populations. Approximately 1 in 54 children in the United States are diagnosed with autism spectrum disorder ASD; . ASD is The bilingual experience is thought to have influences beyond language processing; however, it was initially assumed that these consequences were negative. Despite past assumptions that learning multiple languages may cause confusion and disruptions in language development, current findings demonstrate no differences in language acquisition, proficiency, and achievement of milestones between monolingual and bilingual typically developing children . Furtherbilingual advantage and others failing to find significant effects in typically developing children and neurotypical adults , ventrolateral PFC and inferior frontal junction, the inferior parietal lobule, posterior inferior temporal lobes, and parts of the midcingulate gyrus  assessing bilingualism in 9–10-year-old typically developing children does not support the bilingual advantage hypothesis for inhibitory control, attention switching, or cognitive flexibility  methods in typical populations have also resulted in mixed findings. Limited existing neuroimaging studies suggesting a bilingual advantage are underpowered, report statistically nonsignificant differences in executive function task performance across monolingual and bilingual groups, and fail to directly relate brain activation with behavioral performance . More reThe presence of a bilingual advantage in non-linguistic processes, particularly within the executive function domain, have been brought into question by many studies in which differences between bilinguals and monolinguals cannot be consistently replicated. Literature on bilingualism and executive function is proposed to be affected by a confirmation bias to report only positive results . FindingNonetheless, current research investigating a potential bilingual advantage among neurotypical populations aligns with the conclusion drawn from The extent to which bilingualism confers advantages in the executive function domain in the general population is still an ongoing topic of debate and warrants further research. Conflicting findings in the literature have led researchers to argue whether the bilingual executive function advantage might be restricted to specific groups of individuals or contexts . The mosOlder adults display reduced efficiency of lateral prefrontal control regions and counteract for age-related declines in executive function task performance by relying on enhanced frontotemporal connectivity compared with younger adults . The defcognitive reserve has been observed, where the bilingual brain is more resistant to neurodegeneration and dementia  were more likely to have significantly reduced parent-reported executive function difficulties on inhibitory self-control and flexible switching compared with monolingual children with ASD.The extent to which bilingualism is associated with enhanced executive function abilities in developmental clinical populations is debated. Bilingual research in the executive function domain among individuals with ASD remains sparse. There is a growing but limited body of research examining the performance of bilingual children with ASD on directly assessed measures of executive function. A recent study investigating the relationship between bilingualism and executive function abilities in 6–9-year-old children with ASD with the dimensional change card sort task (DCCS) and the BRIEF parent report of executive functioning in daily life, found a tentative advantage in cognitive flexibility among 20 bilingual children with ASD compared with their monolingual peers . Li and Future directions for this area of research include an increased attention to measurement issues. Laboratory-based measures of executive function tasks may have insufficient predictive value to actual participant ability in the real world . For insDespite bilinguals and monolinguals being treated and compared as two uniform and distinct groups, it is rare that two bilinguals are the same . There iIt is also important to note that not all children with ASD exhibit the same profile and severity of executive function deficits. This heterogeneity makes accurate assessment of ability all the more critical. Comorbidity with other conditions such as ADHD are very common among children with a primary diagnosis of ASD . ExecutiFuture directions should explore brain mechanisms supporting putative bilingual executive function advantages in children with autism to better understand the neural circuitry underlying this phenomenon and understand how bilingualism differently affects the development of executive function systems in the brain of children with ASD. While a bilingual executive function advantage has been demonstrated in certain circumstances, the mechanisms that underlie this advantage remain elusive. Similarly, it remains unknown to what degree the development of a bilingual advantage for executive function is sensitive to IQ and age effects including acquisition age. For instance, a bilingual executive function advantage may only develop as a result of early exposure where both languages are used and activated in parallel for a long period of time. However, it may also be possible that the acquisition of a second language later in life is enough to influence executive control mechanisms. Future work should explicitly study the impact of IQ and developmental effects on the development of a bilingual advantage for executive function.The ambiguous state of bilingualism research is not limited to executive function and extends to other aspects of mental functioning, such as theory of mind, which is commonly compromised in individuals with ASD . Theory Qualitative research on bilingual children with ASD demonstrates a discrepancy between evidence and instruction given to parents . DespiteAfter ASD diagnosis, bilingual children experience a rapid reduction in native language input, even though the use of the home language is persistent in adult-adult and adult-sibling interactions. The decision to restrict their bilingual child’s learning environment may have significant implications . For manThe limited research available presents predominantly converging results on the relationship between bilingualism and executive function advantages in ASD. Developmental outcomes of bilingual and monolingual children on the autism spectrum are comparable. Recent large-sample behavioral studies of neurotypical adults and typically developing children do not support the bilingual advantage hypothesis. However, bilingualism may provide cognitive benefits in specific cases. For example, there is strong evidence that bilingualism acts as a protective factor and may buffer against cognitive decline and dementia. Likewise, bilingualism can bolster executive function in young children, particularly of low SES. And finally, there is preliminary evidence suggesting that bilingualism may ameliorate executive function difficulties in some children with ASD. This research in cognitive development and aging thus suggests that bilingualism might confer an advantage when executive function abilities are still developing, or in clinical populations where executive function is compromised. Thus, bilingualism, under the right conditions, may act as a protective factor for certain executive function difficulties.The current review identified several topics that need to be addressed in future research. Firstly, the use of standardized objective proficiency measurements is strongly recommended. Measurement issues complicate the assessment of executive function difficulties and their neural basis as different combinations of laboratory-based measures, neuropsychological tests, and informant-reports have been used across studies. Future directions should include addressing these issues of measurement in order to maximize ecological and construct validity in research on the relationship of executive function and bilingualism. Secondly, detailed descriptions of the bilingual participants are necessary and individual differences should be better accounted for. Further work is needed to explore heterogeneity and comorbidity in order to better characterize relationships between bilingualism, executive function, and its neural representation in ASD.Celia Romero: Conceptualization: Equal; Writing – original draft: Lead; Writing – review & editing: Equal. Lucina Q. Uddin: Conceptualization: Equal; Visualization: Equal; Writing – original draft: Supporting; Writing – review & editing: Equal.


The processes that drive naive multipotent stem cells towards fully differentiated fates are increasingly well understood. However, once differentiated, the mechanisms and molecular factors involved in maintaining differentiated states and associated transcriptomes are less well studied. Neurons are a post-mitotic cell-type with highly specialised functions that largely lack the capacity for renewal. Therefore, neuronal cell identities and the transcriptional states that underpin them are locked into place by active mechanisms that prevent lineage reversion/dedifferentiation and repress cell cycling. Furthermore, individual neurons may be very long-lived, so these mechanisms must be sufficient to ensure the fidelity of neuronal transcriptomes over long time periods. This Review aims to provide an overview of recent progress in understanding how neuronal cell fate and associated gene expression are maintained and the transcriptional regulators that are involved. Maintenance of neuronal fate and subtype specification are discussed, as well as the activating and repressive mechanisms involved. The relevance of these processes to disease states, such as brain cancers and neurodegeneration is outlined. Finally, outstanding questions and hypotheses in this field are proposed. Summary: This Review explores recent progress in understanding the mechanisms that maintain neuronal cell fate and gene expression, discussing the activating and repressive factors involved, relevance to disease, and outstanding questions. Multicellular organisms are comprised of multiple highly specialised cell-types that confer unique biological functions. These cells are derived via the process of differentiation from multipotent precursors. This is (on the whole) a uni-directional process; differentiated cells once derived, rarely revert to more naive states. Differentiation requires the coordination of transcriptional programmes that promote the expression of genes required for a cell's specific biochemical activities within the context of the functioning organism. These programmes involve the timely activation of required genes, as well as repression of inappropriate gene expression. The processes required to promote distinct cell fates are well-studied. However, once differentiation has been established, there is less appreciation for the subsequent mechanisms that maintain cells in their mature states.Differentiated neurons are post-mitotic cells; having exited the cell cycle, they lack the ability to further divide. Many organisms’ nervous systems have limited regenerative capacity, i.e. they are unable to produce new neurons in adulthood, meaning that neurons born in their early life-stages persist for the entire lifespan without replacement. This means that the gene expression programmes that are required for coordinating nervous system function must be maintained over years or decades  – thereby overriding the gene expression programmes responsible for maintaining the cells differentiated state . This woDrosophila have indicated that differentiated neurons may be reverted to stem-cell like states by removal of key transcription factors , also causes ectopic expression of stem cell genes in Drosophila (RNF113A) was sufficient to rescue the ectopic gene expression seen in mdlc mutants, indicating that neuronal cell-fate may be maintained by conserved mechanisms in mammalian neurons.Several studies in  factors . Loss ofed cells . Crucialed cells A,B. Therosophila . In thisLola mutations were only sufficient to cause dedifferentiation in neurons of the optic lobe , neurons are able to proliferate, but do not lose neuronal markers, thereby lending support for the idea that neuronal cell fate and cell-cycle exit are regulated via distinct mechanisms , are stably expressed for the lifetime of the neuron. The specification of neuronal subtype identity is determined by lineage specific transcription factors during differentiation. However, these genes, known as terminal selectors, continue to be expressed in mature neurons suggesting that they are also required for maintenance of neuronal identity.C. elegans, in which the well-defined nervous system and genetic tractability have facilitated the study of the properties of anatomically and functionally characterised groups of neurons. For example, the terminal selector ast-1 specifies the dopaminergic subtype, and moreover; loss of ast-1 in mature dopaminergic neurons was sufficient to cause these cells to lose their dopaminergic identity   . Therefor cells) , and has elegans  and mous elegans . While mASE-fate . Similar neurons . Therefoche-1 promoter, suggesting that further co-factors may be required to reinforce terminal selector expression. Besides autoregulation, there may be other mechanisms that operate redundantly or uniquely for different factors to ensure sustained neuronal gene expression. For instance, recent research has shown that conserved homeobox (HOX) family transcription factors, which are best known for their role in developmental patterning, are required to maintain cholinergic identity in C. elegans motor neurons  . By this neurons . HOX genFully differentiated neurons house the entire genome of an organism within their nuclei. Of this full complement of DNA, only some genes and regulatory elements are needed for neuronal function. This includes broadly expressed housekeeping genes that are necessary for cell survival, as well as a more restricted set of neuronal genes required for the specific biology of this highly specialised cell-type. Ectopic expression of non-neuronal genes is likely to cause deleterious effects; therefore, the expression of these genes must be suppressed throughout the lifetime of the neuron.in vivo of accessible loci by a transgene expressed DNA adenine methylase (Dam) to show that overall chromatin accessibility becomes increasingly restricted as neural lineages differentiate more fully  or repressed (closed/inaccessible) . Recent re fully . Therefostrained . There i elegans . EctopicChromatin accessibility assays may provide valuable insights into neuronal epigenetic landscapes and can be used to infer specific transcription factors involved in differentiation. However, these assays do not specifically reflect the nature of the changes to the underlying chromatin that coordinate different transcriptional responses. More targeted descriptive studies have shed light on these processes. For example, more complete maps of major histone modifications have been produced for neuronal lineages, either by assessing histone modifications with ChIP-seq from sorted populations of cells , or moreDrosophila showed that five major chromatin states underlie gene regulation which undergo dynamic transitions as neuronal lineages differentiate  components was sufficient to cause stochastic loss of neuronal identity in several neuronal subtypes  known to be involved in human glioblastomas was sufficient to produce proliferating gliomas (Neuronal dedifferentiation has been implicated in the aetiology of certain human cancers. In a mouse model, neuron specific knockdown of two genes ( gliomas . The celWhile these results are strongly suggestive of the possibility of dedifferentiated neurons being the point of origin for some brain tumours, the extent to which this actually occurs in humans is still not fully understood . The abiin vitro differentiated neurons from Alzheimer's patients appear less capable of maintaining differentiated cell fates (A growing body of evidence points towards the loss of mechanisms conferring robust neuronal identity being a major contributor to neurodegenerative disorders. For example, there is extensive evidence that in Alzheimer's disease neurons may begin to display dedifferentiation-like characteristics such as expression of cell-cycle genes , while ill fates . Rather ll fates .The consequences of the disruption of neuronal maintenance may also be apparent in ageing neurons generally, without being associated with a specific pathological state. Studies in model organisms have suggested that a major contributor to ageing is the loss of cell's epigenetic status , and altIt is increasingly clear that the maintenance of neuronal states is an active process that continues throughout the lifetime of the cell to prevent aberrant gene expression leading to pathological states. However, several outstanding questions must be addressed to fully understand the maintenance of neuronal gene expression and associated cell-fate.in vivo to obtain complete mechanistic insight into these processes.The loss of transcription factors required to prevent dedifferentiation or ectopic expression of lineage-inappropriate genes may produce phenotypes only in newly born neurons . SimilarOnce repressive epigenetic environments have been initialised during neuronal maturation, how are these states maintained over long timescales? It is possible that the gradual loss of epigenetic markers seen during ageing is simply due to entropy of chromatin that has no active mechanisms to restore histone modifications at loci where these marks have been lost over time . AlternaAs noted earlier, the fact that many factors responsible for suppressing the expression of non-neuronal genes also promote neuronal gene expression suggests that there may be a constant pool of sequence-specific transcription factors that may be able to bind to loci that become accessible over time due to loss of repressive marks, thereby promoting the re-establishment of the appropriate histone marks or nucleosome positioning. However, it remains unclear whether any necessary co-factors that modify the activity of these factors in a context-specific manner continue to be expressed.It will be necessary to answer these questions to gain a complete understanding of how neuronal transcriptomes and associated cell-fate is maintained in mature tissues. With improved knowledge of these mechanisms, targeted development of therapeutics to treat disorders involved in misregulation of neuronal transcription may be possible. Whilst this Review has focused on neurons, the principles by which differentiated transcriptomes are maintained are likely to be shared across many tissues outside of the nervous system.


In addition to many positive effects of the rise of digitization, its dark sides have also been recognized such as problematic usage of the internet (PUI), smartphone addiction or no-mobile phobia (nomophobia). In 2020, the World Health Organization (WHO) formally recognized and labeled digital device addiction as a widespread problem as online activities and compulsive internet use (or problematic usage of the internet) can affect a significant proportion of the whole population worldwide  as seen above  seem to be predecessors of the phenomena as well as (the lack of) parental control or family conflicts (poor children-parents relationships) but results are inconclusive , holism (ability to coordinate with others) and harmoniousness , which seems to be protective against PUI through mediating maladaptive cognition  was strongly related to PUI highlighting the potential role of selective attentional processing at the background of compulsive internet use.Boredom can easily be alleviated by digital devices. Boredom susceptibility is a relatively rarely studied personality trait, which can be a risk factor for compulsive digital device use. A recent meta analysis confirmed the role of boredom on general internet use, but it also can be related to PUI, however, future studies are needed . In their interesting follow-up study Xu et al. showed the significant effect of peer pressure on mobile social media addiction among adolescents, and peer pressure was more likely mediated by self-esteem than self-concept.Mobile phone addiction is also a well-known digital addiction with extensively growing literature. Probablysocial media applications are the most extensively used functions and mobile social media addiction is one of the main determinants of global mobile addiction (Gao et al., Xu et al. including 371 adults aged ≥45 years showed that the feeling of cognitive decline and impaired family relationships can be associated with mobile addiction mediated by the feeling of alienation, opening new horizons in understanding the digital addiction of this age group.Vast majority of digital addictions studies usually recruit adolescents and older individuals are relatively sparsely studied. These populations may have different risk factors and predecessors of compulsive digital use (Ioannidis et al., Ren et al. showed the efficacy of 5G-based teleultrasound robotic diagnostic system in abdominal scanning, which does not require the presence of radiologist. These technologies can apply in underserved areas widening the accessibility of healthcare services.Finally, apart from the above mentioned potential harmful effects, the use of digital technologies open new pathways in patient management. GF: Writing—original draft, Writing—review and editing. AT: Writing—original draft, Writing—review and editing. GE: Writing—original draft, Writing—review and editing.