Although founding and directing an independent research laboratory is often expected of faculty at American universities, there are several barriers to successful completion of this important task. There is little guidance in the literature regarding exactly how to go about starting a research laboratory. The guidance that does exist for faculty often focuses on running research labs in the “hard sciences,” such as biomedical science and engineering, leaving social and behavioral scientists out of such considerations. Additionally, smaller or teaching-focused universities often have little infrastructure or support for starting a research lab, so faculty at these institutions may not know where to begin. These barriers are significant concerns for junior faculty, who are often unprepared for the realities and challenges of starting a successful research lab while obtaining other milestones required of promotion and tenure. We present two examples of recently-formed gerontology research laboratories begun by junior faculty, one in the psychology department of a research university and one in public health at a teaching-focused university. Our case studies present the audience with specific examples, lessons learned, and guidance for starting their own gerontology research laboratory in higher education, as well as recommendations on maintaining its functioning during a global pandemic (COVID-19).


With these advances, elucidations can be made into how ECM remodeling and more specifically, altered cell-ECM adhesions, regulate tumor growth and cancer cell plasticity. Such enabling tools in mechanobiology will identify fundamental mechanisms in cancer progression that eventually help develop preventative and therapeutic treatment from a clinical perspective. This review will focus on current platforms engineered to mimic the micro and nano-properties of the tumor microenvironment and subsequent understanding of mechanically regulated pathways in cancer.Breast cancer remains a significant burden with 1 in 8 women affected and metastasis posing a significant challenge for patient survival. Disease progression involves remodeling of the extracellular matrix (ECM). In breast cancer, tissue stiffness increases owing to an increase in collagen production by recruited cancer-associated fibroblasts (CAFs). These stromal modifications are notable during primary tumor growth and have a dualistic action by creating a hard capsule to prevent penetration of anti-cancer therapies and forming a favorable environment for tumor progression. Remodeling of the tumor microenvironment immediately presented to cells can include changes in protein composition, concentration and structural arrangement and provides the first mechanical stimuli in the metastatic cascade. Not surprisingly, metastatic cancer cells possess the ability to mechanically adapt, and their adaptability ensures not only survival but successful invasion within altered environments. In the past decade, the importance of the microenvironment and its regulatory role in diseases have gained traction and this is evident in the shift from plastic culture to the development of novel biomaterials that mimic  As cancer, particularly metastasis, remains a leading cause of death globally , there iTME refers to the cellular  and non-cellular (proteins that make up the ECM) components that form the microenvironment of a tumour. In this review, we focus on the non-cellular component, the ECM, present in all tissues and providing the physical scaffolding and biomechanical cues required for tissue morphogenesis, differentiation and homeostasis. The ECM consists of a multitude of proteins  and glycosaminoglycans/proteoglycan . Utilising certain cell membrane receptors  cells can adhere to specific ligands expressed on the ECM. In this way, cells and the microenvironment maintain a dynamic dialogue, whereby healthy tissues remain in a state of homeostasis. This crosstalk is disrupted in tumorigenesis, where extensive remodification to the TME results in altered cell behaviour . The ECMChanges to tissue stiffness following tumor development is one of the most well-established characteristics of the TME and this knowledge is exploited during cancer screening  . Tumor sPrevious investigations into the effects of stiffening on cancer phenotypes arose from the common consensus that tumors are stiffer than their healthy counterpart. However, the TME, and more specifically the ECM, has displayed levels of complexity not previously appreciated. A recent investigation into the nanoscale stiffness of breast explants revealed non-metastatic tumors with this characteristic increase in stiffness, but metastatic tumors with a “softer” more “heterogenous” stiffness profile with 3 distinct mechanical properties . These nIn diseases where ECM is misregulated, changes to ECM composition results in changes to the ligand presentation  have also proven essential in cancer progression. Hyaluronan is a GAG that is highly expressed in breast cancer . HyaluroCompositional remodeling due to increased deposition of ECM proteins, enhanced cross-linking by LOX and localized degradation by secreted MMP factors, has an implication in altering the spacing between individual ligands (e.g. GFOGER). Cells sense the variations in the spacing of ECM proteins through either single integrin proteins or recruitment of larger integrin-containing adhesion complexes . This spIn vitro studies have shown when periodicity is increased above 73 nm melanocytes and osteoclasts were inhibited in their ability to cluster integrins  . The draFor these reasons, semi-synthetic materials such as gelatin methacryloyl (GelMA), synthesized from denatured collagen, has gained significant traction . ContainThe use of these hydrogels allows for high throughput fabrication of readily adaptable and physiologically relevant environments, making it appealing for the study of ECM for cancer proliferation and invasion. Other approaches to mimicking the 3D microenvironment include 3D bioprinting which is beneficial in creating an exact replication of target tissue with consideration for cellular components, ECM and 3D spatial components . AlternStiffness is just one ECM characteristic supplying biophysical input to the cell. Tumor progression also proceeds extensive modification to ECM composition  which alters the integrin profile and at the nanoscale alters the spacing at which cells are interacting with ECM proteins .Polyacrylamide is inert in nature and requires conjugation with proteins to enable cell attachment. Using a bifunctional cross-linker sulfo-SANPAH, proteins can be covalently bound to the PA and enable cell attachment . BecauseHyaluronic acid (HA) as a hydrogel has several important advantages including its biological relevance and chemical tunability. HA functional groups can be modified to enable a wide range of cross-linking chemistries, useful for cellular mechanotransduction investigations . Unlike Recapitulating and controlling for the nanoscale properties of the microenvironment remains a great challenge in biomaterials. Photolithography and optical lithography are the two most commonly used techniques in nanofabrication . Howeverin vivo and in vitro studies have examined the initial stages of tumor growth and invasion and begun to outline some of the nano- and micro-scale changes occurring in the TME–including changes to ECM stiffness, ligand chemistry and ligand nanospacing. Micro-scale changes, such as stiffness and ligand chemistry, have shown greater advancements in biomaterials than nano-scale properties where the primary obstacle has been developing tools in vivo to examine these changes and establishing platforms in vitro that allow for tuneability at this level. Overall, intelligent design of synthetic and biological biomaterials should incorporate these properties so that investigators can focus on the crucial differences between these properties and appreciate the role of the ECM and its regulation of cell fate even at the smallest, and perhaps most crucial, of metrics.The phenomenon responsible for the successful spread of primary cancer cells from their tumor microenvironment to secondary sites is still largely uncharacterized at the molecular level. Universally, the metastatic cascade employs mechanical challenges in which cancer cells will morphologically adapt to survive in these altered environments . Numerou


When considering stem cells (SCs), such a SC niche is a major provider of various cues that influence the cells’ phenotypic potential. In the second volume of this Research Topic contributors presented different examples of how specific microenvironmental effects can be harnessed in developing therapeutic approaches for metastatic bone cancer and diseases of the central nervous system (CNS), as well as emphasizing immune-centric and niche-based targeting. One contribution provides information on importance of a biomimetic Di Pompo et al. present results on development of a potential therapy against metastatic bone osteolysis. In order to metastasize, cancer cells (CC) have to survive their detachment from the primary tumor tissue. This mostly affects dampening of the increased rates of reactive oxygen species and ability to increase the intracellular NADPH levels  by osteoblasts and inducing resident osteoclast precursors to migrate and differentiate into osteoclasts. This further degrades bone tissue and allows further penetrance of CCs. The study is mostly based on in vitro data, while data from xenograft models and patient bone metastasis, showing significant correlation of the osteolytic marker TRACP5b with IL-8, is also provided. Di Pompo et al. suggest neutralizing antibodies against IL-6 or IL-8 as a potential therapy against metastatic bone osteolysis. However, it would also be fascinating to investigate whether bone metastasis could be inhibited by modifying the local microenvironment through cancer metabolism targeting .In their original research study H levels . Once thH levels . MetastaBerlet et al. present a literature review in which they discuss different regenerative therapies as possible treatment options for CNS disorders, such as stroke, Parkinson’s and Huntington’s diseases. These might involve SC therapies, utilizing embryonic SCs (ESCs), induced pluripotent SCs (IPSCs), neuronal progenitor SCs (NSCs) and/or mesenchymal SCs (MSCs) building on their potential to reconstruct the neural circuitry or bystander effects to modulate the immune response. Berlet et al. provide a comprehensive overview on regenerative medicine for treating CNS disorders, focusing on discussing how these strategies can be improved by an enriched environment and exercise. The literature review emphasizes that such an approach can be indeed of great therapeutic value, by improving survival and functional integration of immature cell grafts within the host environment as well as stimulating endogenous repair mechanisms. This was found to be predominantly relevant for stroke and Huntington’s disease. Overall, this article emphasizes the importance of the host environment for therapeutic success of SC therapies.Following the topic of harnessing the environmental effects for therapeutic purposes, Garg et al. analyze the role of inflammation in tissue regeneration, aiming to provide an integrated view, based on analysis of ample relevant literature, on how crosstalk between components of the immune system and SCs in tissue niches impacts tissue behavior during development, aging, and injury. In a complex and comprehensive essay, the authors lead us through different aspects of innate immunity  and their impact on SC fate decision. They further discuss the role of inflammaging, a chronic low grade systemic inflammation associated with aging, and a phenomenon of inflammation-triggered transdifferentiation in homeostasis and stress response. Finally, the authors conclude with the call for further research to expand our knowledge and understanding of intricate tissue niche-specific factors influencing SC decisions in order to envisage immune-centric and niche-based targeting approaches for novel regenerative therapeutic strategies.However, a discussion on environmental factors in tissues cannot be developed without talking about inflammation. One could argue that there is practically no tissue dynamics without some form of inflammatory process . In a wiin vivo microenvironment, both in physiological and pathophysiological conditions, is also voiced by Flagelli et al. in their interesting research report. As emphasized earlier, in vivo microenvironment is a very complex system, particularly so for CNS that is composed of various cell types. 2D models have a limited ability to provide adequate biomimetic analog of a 3D CNS microenvironment which is why extensive research efforts are being directed towards development of 3D models that could recapitulate more efficiently various stimuli found in vivo  differentiation from multipotent NSCs, towards premyelinating and mature myelinating oligodendrocytes (OLs). The device provides a new 3D culture microenvironment, based on the fiber-matrix made of PBT, an inert and biocompatible synthetic polyester. Such fiber mesh was functionalized with a laminin coating, as laminin is one of the main ECM components thus further increasing the mimicking of the NSCs’ in vivo niche. In such a device, mechanical and biochemical cues provided by the fibers and laminin-coating, strongly accelerated maturation of OPCs and their differentiation to OLs that even spontaneously wrapped the fibers in a myelination-like morphology. It will be exciting to see further developments of this device prototype towards a microfluidic system and eventually a bioreactor that could be used as a preclinical platform for axon myelination assays and drug testing in demyelinating diseases.A call for further research towards more precise and accurate 3D model systems that can mimic  in vivo . In theiOverall, this Research Topic once more confirms the importance of the microenvironment for disease development, sustainability and treatment and points to the yet unexplored areas of research in the field.


Women continue to face a greater lifetime morbidity and mortality from stroke and have been shown to respond differently to stroke treatments compared to men. Since 2016, updated National Institutes of Health (NIH) policies require research studies to consider sex as a biological variable. However, the way in which this policy affects study design, analysis, and reporting is variable, with few studies performing and reporting a subgroup analysis based on biological sex. In acute ischemic stroke, the underlying biological explanation for sex-based differences in patient outcomes and response to treatments remains understudied. We performed a systematic review of preclinical and clinical research studies that explored sex differences in the metabolic response to acute ischemic stroke as it relates to neurological outcomes. Through a literature search in Ovid Medline, Embase, and Web of Science, 1,004 potential references were identified for screening. After abstract and full-text review, we identified only two studies which assessed metabolic response to acute ischemic stroke (within 72 h of last known well) and neurological outcome  and reported results based on biological sex. One article was a preclinical rat model and the other a clinical cohort study. In both studies, metabolites involved in amino acid metabolism, energy metabolism, fat metabolism, or oxidative stress were identified. We review these results and link to additional articles that use metabolomics to identify metabolites differentially expressed by sex or regulated based on stroke outcomes, but not both. The results of this systematic review should not only help identify targets in need of further investigation to improve the understanding of sex differences in the pathophysiology of acute ischemic stroke, but also highlight the critical need to expand the incorporation of sex as a biological variable in acute stroke research beyond simply including both sexes and reporting the proportion of males/females in each population studied. Stroke remains a leading cause of death and disability worldwide with the majority being ischemic in nature . DespiteThe pathophysiology of stroke and the resulting total infarct volume are metabolically active events. After the onset of ischemia, there is a complex set of molecular events that begin within minutes to hours and ultimately result in neuronal cell death. These events are initially driven by decreased blood flow and hypoxia, but are quickly followed by tissue depolarization and a subsequent increase in metabolic rate. Coupled with an already low oxygen supply and compromised cerebral blood flow, this creates a hypoxic environment that perpetuates tissue destruction and infarct size , 3. TissDespite a basic understanding of the pathophysiology of stroke, the exact mechanisms and metabolic response to ischemic stroke have not been fully elucidated. Improved understanding of this metabolic response and identification of potential mechanisms to salvage penumbral tissue may lead to future therapeutic advances. Currently, treatment for acute ischemic stroke is limited to either intravenous thrombolysis with a tissue plasminogen activator (tPA) such as Alteplase or Tenecteplase, or endovascular therapy with direct clot lysis or mechanical thrombectomy. These acute therapies have limited treatment windows and it is estimated that only 10–15% of patients presenting to either a comprehensive or primary stroke center receive tPA with only 1–4% receiving endovascular therapy . FurtherMetabolomics – the study of small downstream targets that reflect upstream metabolic processes – has the power to inform the biology of acute ischemic stroke and lead to novel therapeutics. Metabolomics has been used to differentiate between types of stroke  –12, tranThis systematic review was conducted with close attention to the PRISMA  guidelines  , and Web of Science Core Collection . The search was constructed for Ovid MEDLINE and translated to the additional databases. All results were exported to and deduplicated in EndNote 20. Covidence systematic review software  was used for screening and full text review. See A comprehensive literature search was designed and performed by an experienced medical librarian (CP) in May 2022 for the concepts of metabolomics and ischemic stroke. Relevant publications were identified by searching the following databases with a combination of standardized index terms and keywords: Ovid MEDLINE ALL , Embase  had to be reported. For targeted metabolic studies, a metabolite was defined as a small molecular substance involved in metabolic processes as previously identified in the Human Metabolome Database  independently screened all titles and abstracts and subsequent full-text articles. Data were compiled and consensus was reached by discussion on any disagreements for exclusion. Quality assessment of studies was done using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) protocol for animal data  spectroscopy of serum samples to determine the metabolic response to MCAO and a 10-day pretreatment with Huang-Lian-Jie-Du Decoctin, a traditional Chinese medicine used to treat cerebral ischemic/reperfusion injury, compared to controls. In the clinical study, serum samples were collected within < 72 h (most were collected within 24 h) from stroke onset. Targeted analysis of tryptophan  was performed using high performance liquid chromatography (HPLC) to identify metabolites associated with stroke and neurological outcomes.One thousand four study titles and abstracts were screened for inclusion. One hundred forty-six full-text studies were assessed for eligibility with the majority being excluded for more than one reason  see , one wasThe preclinical analysis of sex-specific response to middle cerebral artery occlusion (MCAO) with or without treatment with Huang-Lian-Jie-Du Decoctin was determined to be of moderate-high quality with low risk of bias based on the CAMARADES approach which is specific to ischemia models and includes assessment of sample size calculations, randomization and blinding, the use of anesthetic without intrinsic neuroprotective activity, and control of temperature during ischemic experiments . Zhang eFew preclinical studies of ischemic stroke included both male and female rodents. In Zhang et al. , authorsvia the TCA cycle to anaerobic metabolism. In male MCAO rats, the almost 20% decrease in phosphocreatine and slight increase in creatine also supports a TCA cycle failure. Increased conversion of phosphocreatine to creatine can supply the high energy bond in phosphocreatine to create adenosine triphosphate (ATP). These data suggest that the imbalance of energy metabolism and the production of ATP may be more impacted in male MCAO rats compared to females MCAO rats, which did not demonstrate these same changes compared to female controls. Additionally, only male MCAO rats showed a >20% increase in metabolites involved in lipid fatty acid β-oxidation compared to controls .In terms of energy metabolism, lactate was increased in male, but not female MCAO rats, compared to control rats. Citrate, pyruvate, glucose, and malate were overall lower in MCAO rats compared to controls. These metabolites, in conjunction with lactate, are integral in energy metabolism and changes in concentration can reflect a shift from aerobic metabolism In contrast to the male-specific changes in energy and lipid metabolism, female MCAO rats exhibited a greater change in amino acid metabolism compared to controls, which was not seen in males. Specifically, female MCAO rats had higher levels of aromatic amino acids  compared to female controls, while male MCAO rats exhibited no significant change compared to male controls. In females, MCAO rats also had slightly higher levels of N-acetylaspartic acid compared to controls whereas in males, MCAO rats showed a significant decrease compared to controls.Despite multiple notable differences in metabolic response to MCAO between males and females, this study did not directly link these metabolic changes to different neurological outcomes. Rather, authors reported differential metabolomic profiles and differential neurological function independently. However, many of the differences in metabolic profiles support the relatively preserved neurological function after MCAO in female rats compared to males MCAO rats. The caveat in terms of translation to humans being that this study did not use aged rats. This allows for preserved estrogen effects in female rats that might not recapitulate the precise sex-differences in metabolic response to stroke in human post-menopausal women. While this study was an overall robust study in its design with the use of sham and placebo groups, comparison of serum and cerebral tissue metabolomic profiles, it remains limited by a lack of a priori sample size calculations and the need for further in-depth confirmation of the importance of the metabolic changes identified.via the kynurenine pathway is associated with worse neurological function. Females with stroke also showed higher levels of the downstream kynurenine pathway metabolite quinolinic acid, higher levels of the ratio of quinolinic acid to kynurenic acid, and lower levels of a tryptophan index. The tryptophan index {100x[tryptophan/]} reflects the balance between tryptophan and other amino acids that compete with tryptophan for transport across the blood brain barrier. Together, this would suggest that females have higher rates of metabolism via the kynurenine pathway which may correlate with worse neurological function. However, again, there was no sex-based subgroup analysis of functional outcome, nor was there a direct analysis of functional outcome as it related to tryptophan metabolism in male stroke patients compared to female stroke patients.Like many preclinical models, which often do not report results based on biological sex when they do include both sexes, few clinical studies in stroke go beyond reporting cohort demographics . Ormstadvia the kynurenine pathway into multiple metabolically active compounds with both neurotoxic and neuroprotective roles. Tryptophan is primarily converted to kynurenine. Kynurenine is subsequently metabolized via either a neuroprotective pathway, which dominates under normal conditions, or a neurotoxic pathway, which dominates in response to pathological conditions. Under pathological conditions, high levels of proinflammatory cytokines stimulate the conversion of tryptophan to kynurenine. This shifts the pathway toward the neurotoxic branch  and an American Heart Association Career Development Award .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Therapeutic hypothermia (TH), or targeted temperature management (TTM), is a classic treatment option for reducing inflammation and potentially other destructive processes across a wide range of pathologies, and has been successfully used in numerous disease states. The ability for TH to improve neurological outcomes seems promising for inflammatory injuries but has yet to demonstrate clinical benefit in the intracerebral hemorrhage (ICH) patient population. Minimally invasive ICH evacuation also presents a promising option for ICH treatment with strong preclinical data but has yet to demonstrate functional improvement in large randomized trials. The biochemical mechanisms of action of ICH evacuation and TH appear to be synergistic, and thus combining hematoma evacuation with cooling therapy could provide synergistic benefits. The purpose of this working group was to develop consensus recommendations on optimal clinical trial design and outcomes for the use of therapeutic hypothermia in ICH in conjunction with minimally invasive ICH evacuation.An international panel of experts on the intersection of critical-care TH and ICH was convened to analyze available evidence and form a consensus on critical elements of a focal cooling protocol and clinical trial design. Three focused sessions and three full-group meetings were held virtually from December 2020 to February 2021. Each meeting focused on a specific subtopic, allowing for guided, open discussion.These recommendations detail key elements of a clinical cooling protocol and an outline for the roll-out of clinical trials to test and validate the use of TH in conjunction with hematoma evacuation as well as late-stage protocols to improve the cooling approach. The combined use of systemic normothermia and localized moderate (33.5°C) hypothermia was identified as the most promising treatment strategy.These recommendations provide a general outline for the use of TH after minimally invasive ICH evacuation. More research is needed to further refine the use and combination of these promising treatment paradigms for this patient population. Intracerebral hemorrhage is characterized by bleeding within the parenchyma of the brain. As blood accumulates in the parenchyma, direct mechanical injury damages surrounding neurons and increases intracranial pressure (ICP). This increased pressure leads to reduced cerebral perfusion and additional ischemic injury . HematomEven after the clot has stabilized, additional neurological damage is caused through secondary injury induced by inflammation, neurotoxicity, and other mechanisms. This secondary injury, which manifests visually as perihematomal edema (PHE), comprises both vasogenic and cytotoxic elements and leads to reduced perfusion, disrupted autoregulation , and celRecent studies have suggested a potential benefit for minimally invasive surgical (MIS) evacuation, a procedure in which a small craniotomy or burr-hole is made and a device is stereo tactically guided into the blood clot to permit evacuation through a small channel under enhanced visualization , 12. TheHypothermia is one of the earliest and most thoroughly studied neuroprotective strategies, exerting its effects through multiple mechanisms –17. AcutSystemic TH is the practice of inducing hypothermia through the reduction of body-core temperature, thereby achieving hypothermia of all organs including the target organ, the brain. Systemic hypothermia can be achieved by multiple modalities including surface cooling , endovascular cooling via venous catheters . No substantial evidence has demonstrated efficacy or superiority of any modality , 23.The application of systemic TH has been studied in multiple conditions that result in neurological injury including post-cardiac arrest , traumatSystemic TH carries specific risks related to the lack of organ-specific targeting. Shivering is common amongst systemically cooled patients, thereby requiring the use of high-dose sedatives to minimize delays in reaching target temperatures. Increased rates of infection, particularly pneumonia, are significantly associated with systemic TH, which may be partially explained by TH impairing leukocyte function and T-cell activity –37. OtheGiven the limitations of systemic TH, the development of regional cooling devices and protocols have sought to avoid the side effects of full-body cooling while still incurring the benefits of TH. Surface cooling mechanisms including cooling caps and neckbands have been found to successfully achieve parenchymal temperatures, measured with tympanic probes, as low as 33°C while maintaining core normothermia . IntranaMultiple meta-analyses of preclinical studies have shown the ability of TH to reduce PHE and improve neurobehavioural scores, however, there has yet to be a definitive human study demonstrating efficacy in a clinical setting , 47. SevICH would benefit from the neuroprotection induced through TH, however, given the fragility of the patient population, it is imperative that particular considerations be taken to optimize safety and efficacy. In the case of cardiac arrest and ischemic stroke, treatment is deployed immediately, as patients are frequently in near-catatonic states and substantial evidence indicates the benefits of rapid treatment. The deployment of TH is easily built into these high-level emergencies, as multiple physicians are continuously involved with therapy. Compared to patients presenting with ischemic stroke, ICH patients are considered a lower level of emergency due to the lack of effective treatment, resulting in treatment paradigms focusing on stabilization and monitoring. The induction of early systemic hypothermia in ICH inherently elevates the level of emergency in these patients, increasing the likelihood of complications and requiring additional expert monitoring. TH-induced coagulopathy is also a particular concern, as demonstrated in animal ICH studies .The use of focal cooling may avoid the negative side-effects of systemic cooling, yet the ability to cool deep within the brain via surface or intranasal cooling methods is currently in question. The skull is an efficient insulator, hampering the ability for surface cooling to effectively cool areas of deep injury. High rates of cerebral blood perfusion act to introduce heat to focal cooling systems, potentially limiting the ability of surface or nasal cooling to penetrate to deeper bleeds or areas of injury.The development of MIS techniques to treat ICH introduces a unique avenue to induce focal cooling, as accessing the bleed to perform evacuations inherently allows for access to the primary site of injury. The induction of intracavitary cooling, cooling initiated from within the cavity created during clot evacuation, would efficiently target the PHE core, but may also incur additional risks due to its intracranial deployment. This combination therapy addresses the major destructive mechanisms of ICH by reducing mass effect, removing the iron-rich clot, and reducing the local neuroinflammatory cascade. Multiple clinical trials have already been conducted in China, where MIS-ICH evacuation has already been widely adopted, indicating a benefit of postoperative cooling compared to control .Herein, we present emerging recommendations from the Therapeutic Hypothermia for ICH (‘HICH') Working group. This includes a recommended cooling protocol to demonstrate and optimize TH in ICH that has been evacuated with minimally invasive techniques. Specific procedures for cooling initiation and maintenance are described, as are optimal trial elements.An international panel of experts on TH and ICH was convened to form a consensus on critical elements of a focal cooling protocol and the outline of a systematic pathway to develop TH as a potential adjunctive therapy in ICH patients undergoing MIS evacuation. The full group met virtually for three sessions from December 2020 to February 2021, with three additional meetings with session leaders prior to each full meeting. Each meeting focused on a specific topic and was led by group members that specialized in the focus. Prior to each meeting members were asked to complete a questionnaire outlining their views, which were combined into a short presentation to guide discussion. Meeting topics included: (1) General outlook of the field , (2) best cooling procedures for focal use of TH in conjunction with ICH evacuation , and (3) key trial design characteristics for assessing benefit through feasibility and pivotal trials . Meetings were open-forum, allowing for open discussion on each assigned topic. All discussions were recorded and an outline of each discussion was written and shared with the entire group for review.The following recommendations  are baseHistorically, clinical use of TH with ICH has involved systemic hypothermia despite the inherent limitations of secondary complications. The recommended cooling protocol implements a combination of both systemic nor-mothermia with localized intracerebral hypothermia. This technique has already gained traction in ischemic stroke, where endoscopic localized cold infusions are used to improve reperfusion injury. Numerous preclinical ICH studies have also connected localized cooling to significant reduction in edema. This should allow for the induction of inflammatory inhibition while minimizing the negative effects associated with non-specific organ cooling. Further innovation is required as there is currently no approved clinical device or mechanism to induce local cooling following ICH.We recommend that mild systemic cooling be initiated while the patient is being prepared for surgery, immediately before the initiation of anesthesia. The neuro-inflammatory pathway associated with ICH initiates immediately upon injury, and early targeted temperature management to stem the initial cascade prior to evacuation may be beneficial. While some preclinical studies have demonstrated increased hematoma growth in response to profound cooling, meta-analyses have routinely failed to show a significant relationship between cooling and hematoma expansion, particularly when cooling is kept above 33°C , 54. It We recommend the patient be cooled systemically with a controlled feedback loop to nor-mothermic levels with a target temperature of 36.5°C. Surface cooling appears the optimal mechanism as normothermia in most cases does not induce shivering, rapid cooling is not required, and therefore reduces the need for endovascular cooling mechanisms. Temperature selection is intended to (1) reduce fever burden, (2) minimize the risk of temperature-induced coagulopathy, and (3) maximize the cooling ability of the localized hypothermia to be induced intraoperatively.Systemic normothermia should be continued throughout the surgical procedure via the same cooling techniques employed preoperatively. Localized intracerebral cooling should be initiated immediately following completion of the clot evacuation but prior to the removal of the endoscope. This will allow for direct monitoring of the hematoma cavity for TH-induced re-bleeds and confirmation of successful cooling of the injury core. Local cooling and systemic normothermia should continue until the procedure is completed and through postoperative care.We recommend a target local temperature of 33.5°C. Cooling should be induced rapidly, but with a lower boundary of 33°C as preclinical data suggests that coagulopathy issues occur at that temperature . The conBoth intracerebral cooling and systemic normothermia should be continued at target temperatures of 35 and 36.5°C, respectively. Cooling should be maintained for 48 h, which fits within common neurological recovery periods following MIS-IHC evacuation. Upon the completion of the cooling period, rewarming should increase intracranial temperature at a rate of 0.5°C every 6 h. This rewarming rate should be done with special attention paid to intracranial pressure. The entire protocol should ideally conclude 4 days after hematoma evacuation.ICH is a complex condition and the best treatment strategies for evacuation are still under investigation. It is therefore crucial that trials assessing the use of TH in combination with hematoma evacuation be well-considered and thorough. Here we outline a recommended protocol for clinical development program testing the impact of the previously described cooling protocol, as well as a series of future clinical trials to iteratively demonstrate the clinical effects of TH for ICH.The recommended inclusion and exclusion criteria are intentionally heterogeneous to allow for a wider variety of clinical scenarios that may benefit most from this treatment paradigm. This will also ameliorate recruitment struggles, which has led to extended periods for previously published ICH cooling trials , 51. RecPatients with spontaneous supratentorial ICH under age 80 who meet all criteria should be included in the study. This matches standard eligibility criteria for ICH evacuation at established institutions, where most have a cap of 80 years which also has been used as an inclusion criterion in most previous studies. There is no clinical evidence that older individuals suffer more negative effects of systemic or focal TH, and with a majority of ICH patients being over the age of 60 it will be crucial to include older individuals to achieve successful sample sizes.Hematoma size quantification must be conducted prior to patient enrollment, with a recommended minimum bleed size of 20 mL required for trial inclusion. This is a common threshold in standard evacuation protocols, as well as prior systemic TH for ICH trials without evacuation .A minimum Glasgow Coma Scale score of 6 or more is recommended. This is more inclusive than past TH trial protocols but represents the prevailing wisdom within ICH evacuations given the acute nature of treatment. Standard procedures at institutes frequently performing evacuations require a GCS score of 4 or more. It is possible that active profound cooling of certain brain regions may negatively affect immediate postoperative neurological scores, therefore confounding results, so an upper limit of GCS may be required for future trials.While the value of early evacuation is still under investigation, it is clear that TH appears most effective when introduced early after neurologic injury. As certain institutes performing regular evacuations are able to achieve insult-to-evacuation times below 12 h, it is recommended that the initiation of TH for early feasibility and pilot trials be set to 12 h. It is unclear if all institutions would be able to achieve this time course for a larger, multisite trial, so later studies may extend initiation delay to a 24-h maximum. There is preclinical evidence of increased bleeding in response to early induction of low (<33°C) temperatures following ICH induction, however, hematoma evacuation allows for direct control of potential temperature-induced secondary bleeding. The recommended target temperature is also higher than prior research showing increased frequency or severity of re-bleeds.n = 5–10) should focus primarily on the functionality of the cooling mechanism by quantifying the amount of intracranial cooling achieved. Multiple modalities exist to measure this effect, including implantable temperature probes and real-time magnetic resonance thermometry. This early trial should also track device-related severe adverse events (SAE). Cooling-induced coagulopathy leading to secondary bleeding or hematoma instability is a key concern with focal cooling after evacuation, and symptomatic and asymptomatic re-bleeds should be closely tracked. Recruitment rates will serve to validate the previously outlined inclusion/exclusion criteria.Despite extensive preclinical data there has yet to be a controlled study assessing the use of focal hypothermia to improve ICH outcomes in patients , 61. An N = 10–20) will be required to establish safety and efficacy parameters of the proposed protocol. The frequency and severity of secondary bleeding should again be tracked closely and reported on by the study team, as should any other anticipated adverse events. Secondary outcomes should closely track the expansion of PHE volume relative to the hematoma size (rPHE). This should be tracked at the end of active cooling (48 h), at discharge from the neurosurgical ICU (7 days), as well as at a 7 and 30-day follow-up.Having demonstrated the feasibility of local hypothermia in the setting of post-ICH evacuation, a larger pilot trial (Closely controlled hypothermia remains a highly promising avenue for improving outcomes after ICH. The mechanisms behind hematoma removal and brain cooling should theoretically work additively or synergistically, and it is crucial that the field form a consensus on optimal cooling protocols for ICH patients with the data generated from past studies. It is important to note that the recommended cooling protocol described here is designed to minimize risk, and the results of future studies will likely augment and improve both safety and efficacy outcomes. Two primary parameters have been identified in most need of additional research: target temperature and duration of cooling. The combination of these parameters describes a TH “dose.” The use of TH as a treatment paradigm is unique in that a device-centric, physical therapeutic must be dosed appropriately for each pathology. Systemic TH dosage for post-cardiac arrest patients is still under debate, and it is likely that the use of TH in postoperative ICH patients must navigate a similar period of trials, analysis, and debate.Local cooling in conjunction with evacuation has been identified by this working group due to the unique access of ICH evacuation and the synergistic nature of the mechanisms; however, there is no currently available technology to safely and effectively induce this intervention, suggesting the need for further innovation. The local target temperature of 33.5°C was selected to minimize intracavitary coagulopathy risk. The use of highly localized intracranial cooling could allow for more profound cooling as colder temperatures induce significant vasoconstriction, which may offset any temperature-induced coagulopathy . TemperaA cooling duration of 48 h was recommended as it spans the length of key PHE periods, which have been found to expand most rapidly within 6 h of hematoma formation, peaking at approximately 48 h post incidence. Current literature does not conclusively indicate the effect early cooling will have on PHE expansion, however rapid, short-term cooling has been shown to inhibit the development of inflammatory cascades across a variety of pathologies. Future research may show that early induction of TH does enough to stem the evolution of the PHE and associated inflammatory pathways, and therefore would reduce required cooling duration; this would match similar findings with ischemia when treatment occurs during or immediately following ischemia compared to delayed cooling.An injury-to-cooling threshold of 12 h was recommended in an attempt to maximize the overall effect of the cooling on initial inflammation reduction. Ultimately this time point will be decided by the ability of facilities to engage in rapid diagnosis and patient transfer as well as the results of ongoing clinical studies evaluating the safety, feasibility, and efficacy of early evacuation . ExtensiThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.TB, CK, and SM organized and hosted meetings. All authors participated in discussions and as well as drafting and editing of the manuscript.Author NB has received research funding from Becton Dickenson, Maryland Industrial Partnerships, Department of Defense. Author TB owns equity in a start-up investigating mechanisms of local cooling for ICH. Authors TB and CK are listed inventors in IP relating to cooling after ICH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BE declared a shared affiliation with the author PL to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


African swine fever (ASF) is an internationally-spreading viral pig disease that severely damages agricultural pork production and trade economy as well as social welfare in disease-affected regions. A comprehensive understanding of ASF risk factors is imperative for efficient disease control. As the absence of effective ASF vaccines limits disease management options, the identification and minimisation of ASF-associated risk factors is critical to preventing ASF outbreaks. Here, we compile currently known potential ASF risk factors identified through a systematic literature review. We found 154 observation-based and 1239 potential ASF risk factors, which we were able to group into the following defined risk categories: ‘ASF-virus’, ‘Biosecurity’, ‘Disease control’, ‘Environment’, ‘Husbandry’, ‘Movement’, ‘Network’, ‘Pig’, ‘Society’ and ‘Surveillance’. Throughout the epidemiological history of ASF there have been similar risk categories, such as ‘Environment’-related risk factors, predominantly reported in the literature irrespective of the ASF situation at the time. While ASF risk factor reporting has markedly increased since 2010, the majority of identified risk factors overall have referred to domestic pigs. The reporting of risk factors for ASF in wild boar mostly commenced from 2016 onwards. The compendium of ASF risk factors presented herein defines our current knowledge of ASF risk factors, and critically informs ASF-related problem solving. African swine fever (ASF) is a transboundary viral pig disease with a massive socio-economic impact worldwide . The cauOrnithodorus spp.) that co-habits the burrows of warthogs. Transmission to domestic pigs may occur through contact with infected warthogs, feeding on warthog meat, or by the bite of an infected soft tick vector. For transmission independent of direct contact, it is thought that meat products from infected domestic pigs mostly spread the disease to other pigs .,47.46,47Population (P): the study describes domestic or wild pigs exposed to ASFVExposure (E): the examined study population is exposed to a defined risk factorComparator (C): the study describes pigs that are exposed to ASFV but not to the examined risk factor, or a suitable reference scenario is describedOutcome (O): the studied pig population is infected with ASFV as determined by some form of measurementTo identify reported ASF risk factors, this review included as many primary peer-reviewed studies about ASF risk factors as were accessible until the search cut-off date. Thus, no time limitations were applied when retrieving search results other than the limits inherently imposed by the coverage timespan of the utilised databases and the search language. Review articles and editorial-type letters were excluded. Consistent with the language cognition accessible to the reviewer team, records that were not available in English, German, Italian, or Spanish were excluded. To identify relevant studies that included observations about risk factors associated with ASFV infection and risk exposure in pigs, the PECO (Population-Exposure-Comparator-Outcome) principle was applied to structure the necessary criteria of risk exposure reports according to the review objective ,48. BaseIdentified eligible records for which a full text document was not available by 20 November 2020 were excluded from the review.https://pubmed.ncbi.nlm.nih.gov/, accessed on 30 September 2020)MEDLINE via PubMed MEDLINE via Web of Science Scopus EFSA Journal AGRIS Open Theses and Dissertation Networked Digital Library of Theses and Dissertation DART-Europe ” in PubMed or “PUBYEAR > 1700” in Scopus. The known timespan of database coverage or the oldest record retrieved from open search queries (if older than the known year) and their accessed web-addresses were:These databases were selected in order to capture the primary scientific literature in the fields of biomedical sciences, agriculture, veterinary medicine, social sciences, animal sciences, and economical sciences, all of which were deemed relevant for the review objective. Required full-text records were obtained through professional in-house library services utilising online requests and local repository access.http://www.r-project.org, accessed on 28 March 2022) , the, the7], One conclusion that can be drawn from the identified lack of variability among frequently identified risks over time is the need to encourage researchers to stray off the beaten path and help reveal previously unobserved connections between potential risk factors and ASFV infection in pigs. To expand the conventional ASF research focus beyond environment and husbandry risk categories, the list of potential ASF risk factors purposefully assembled here see  may provCategorical enumeration of the identified risk factors highlights that certain risk categories are relatively underrepresented, indicating that factors contained therein have not yet been observed to influence the risk of ASF spread as perhaps expected. ASFV is one of these categories, indicating that pathogen-related factors such as genetic variance potentially provide a much smaller than anticipated basis of observation for informing ASF strain-related risks through molecular tracking of pathogen characteristics and epidemiology .Our systematic literature review revealed that the types of risk factors identified throughout ASF history are categorically similar regardless of the concurrent ASF situation at the time, that risk factor reporting has particularly increased since 2010, and that there is a focus on environmental risk factors in the ASF risk literature, mostly in domestic pigs.As in any literature-based work, the present study has limitations. This systematic review focused on the identification of potential ASF risk factors. Thus, a wide search strategy was combined with selection criteria-based screening and review of records to find as many previously considered risk factors as possible. Of the identified risk factors and studies, we deemed it more important to include a wide range of risk information than to impose stringent restrictions through strict application of quality measures in this context. Specifically, we observed variations in the fulfilment of selection criteria for the PECO-informed selection of records reporting ASFV infection in pigs with exposure to risk factors. The risk of bias on the study level includes variation in study type or the epidemiological context referred to, for example, the country of study. This information may be important for the evaluation of risk factor evidence, which was beyond the scope of this work.Risk of bias in the selection of articles for our library may have arisen from applying selection criteria at initial screening that were too narrow or limiting, such as language specification and exclusion of reviews . We usedThe choice of queried databases and subjective collection of potential risk factor types by the reviewing team could have led to incomplete or non-representative identification of ASF risk information. While these limitations have to be considered in the interpretation of our findings, we judge the overall collection of ASF risk factors in this review to be near complete. This view is based on the following two observations. First, while many of the collected potential ASF risk factors turned out to be similar, these were retained in the final library and many of the originally extracted factors were removed as exact duplicates, indicating saturation of risk factor identification. Second, search string queries of the chosen literature databases initially retrieved 2037 records, yet de-duplication then excluded almost half of these records . This suCategorisation was applied to ASF risk factors, and the decisions with respect to assigning a risk factor to a specific category were to some degree made subjectively despite implementing descriptions for each category  51,67].,67.51,67To exemplify this point, the following cases should be considered. The increased occurrence of diverse ASF risk categories in the literature during distinct time segments is independent of the chosen categorisation due to the influence of data stratification on diversity counts being minimal B. By conThis systematic review identified a comprehensive collection of known ASF risk factors. Our findings can help to guide the identification of previously unrecognised risk factors, reveal research gaps, support the evaluation of ASF management strategies, and inform risk assessments.


Our Research Topic broadly reviewed multiple facets of treating the critically ill patient with acute lung injury (ALI) . There wAcute respiratory distress syndrome (ARDS) was first identified in 1967 but remains a significant medical problem today . Fifty-fRola and Daxon conducted a case series on COVID-19 induced ARDS (CARDS) patients. They showed that the time controlled adaptive ventilation (TCAV™) method to set and adjust the airway pressure release ventilation (APRV) mode was highly effective at stabilizing and then gradually reopening the collapsed and edema filled lungs of CARDS patients. The TCAV™ method [developed by Nader M. Habashi]. TCAV uses inspiratory and expiratory time to rapidly stabilize and then gradually open collapsed tissue over hours or days . They showed the efficacy of this Stabilize Lung Approach (SLA) approach in CARDS patients using chest X-rays, ventilator parameters, and arterial blood gases (ABGs). They also discussed physiologic mechanisms for TCAV efficacy, fine points of TCAV settings, and complexities of training an entire intensive care unit (ICU) team on TCAV™ use. Lastly, they discussed the problem of the “apparent cure” when TCAV™ has a patient’s lung fully recruited with near normal ABGs and respiratory system compliance (CRS) such that they no longer meet the Berlin defined ARDS. If these patients are converted back to conventional mechanical ventilation (CMV) the lungs may rapidly re-collapse.  that represents the volume of expired CO2 in one signal breath can inform clinicians about pulmonary perfusion, end-expiratory lung volume, dead space and ventilation inhomogeneities. Recent work has shown that Vcap can possibly be used to continuously measure end-expiratory lung volume (EELV), lung strain, and effective pulmonary blood flow. The ability to measure all of the above at the bedside would be an incredible tool in the clinicians’ treatment options. Using these parameters, the clinician can modify the ventilator mode and the method necessary to maximize EELV and minimize lung strain that is individualized to each patient. With future development Vcap might be able to optimize lung protective ventilation strategies and reduce VILI-related mortality.T) and positive end expiratory pressure (PEEP) with and without recruitment maneuvers (RM), in an attempt to reduce VILI. Ismaiel et al. used CMV in a rat ARDS model to differentiate the pathophysiologic impact of mechanical and inflammatory injury as VILI mechanisms. They showed that low tidal volume (LVT) strategy reduces VILI by limiting mechanical damage, while hypercapnia limits pro-inflammatory and biochemical mechanisms of injury. They close by suggesting that LVT combined with hypercapnia may work synergistically to reduce VILI.Most protective ventilation research efforts use CMV modes adjusting tidal volume , high frequency percussive ventilation (HFPV), and high frequency jet ventilation (HFJV). Unfortunately, results of this review show no consistent outcomes among modes, nor does it identify an optimal ventilator mode or method for the PARDS patient. They concluded that only high quality randomized controlled trials (RCTs) would be able identify if an optimal ventilation strategy does exist for the PARDS patient but caution that these trials are very difficult to conduct.A review of protective MV for the pediatric ARDS (PARDS) patient by Miller et al. The review covers HFOV theory of operation, mechanics, and characteristics of all ventilators that can deliver the mode. Evidence of HFOV efficacy from bench models, animal studies and in both adult and pediatric patients are reviewed in detail. Although the physiologic rationale for HFOV is sound with many positive animal studies, the mode has lost popularity with both adult or pediatric patients following the failed 2013 OSCAR and OSCILLATE clinical HFOV RCTs  on short term lung function. It has been shown that vPSV, compared with PSV, can improve oxygenation and patient-ventilator synchrony, but these studies were conducted using only one variability level at a fixed pressure support. In this study the addition of multiple levels of variability did not improve oxygenation and high variability levels increased patient-ventilator synchrony.In a crossover clinical trial in 20 patients with mild to moderate ARDS, L) and driving pressure (ΔP) are critical when managing ventilator settings on patients with ARDS, which are often measured clinically using plateau pressure (Pplat). Although this ‘stop flow’ condition is valuable and universally accepted, it may underestimate the maximum stress that occurs in lung tissue under dynamic conditions. Tawfik et al. compared the static measurement of CL and ΔP with another static method and two dynamic compliance measurement methods. The other static method to calculated CL and ΔP the pressure at zero flow and the two dynamic methods used the inspiratory slope during inflation with a constant flow and the expiratory time constant method. They found that the static measurement using Pplat may underestimate the maximum pressure exposed to lung tissue during dynamic inflation. Whereas the static method using zero flow and the dynamic method using inspiratory slope gave a truer estimate of maximum pressure exposed to alveoli. This pilot study suggests further studies are necessary to identify the optimal method to measure CL and ΔP necessary to improve patient outcomes.Accurate measurements of lung compliance , which are specific markers of skeletal muscle damage. The goal was to identify the trend of skeletal troponin during weaning and compare it with fsTnL and ssTnl levels with diaphragmatic ultrasound in healthy volunteers. They found that fsTnL and ssTnl have specific and different trends during weaning with the fsTnL decreasing during the early phase of weaning, while high initial values of ssTnl were correlated with a larger diaphragmatic displacement over time. More work is necessary to identify if these markers can be used to identify diaphragm function in ALI patients.Mechanical ventilation for patients with ALI can lead to ventilator induced diaphragmatic dysfunction (VIDD) . CurrentKrenn et al. reviewed the impact of mechanical ventilation on RAS in the patients with ARDS with the intent of discovering novel biomarkers and possible therapeutic targets . Many clinical trials have been conducted using RAS-modifying drugs in mechanically ventilated ARDS patients and patients with other medical issues, that resulted in positive outcomes. These positive studies suggest RAS-modifying drugs maybe effective treatment of both the primary cause of ARDS as well as the secondary VILI that is associated with increased ARDS-related mortality.There are three major mechanisms of VILI: Atelectrauma , volutrauma , and biotrauma (excessive release of inflammatory mediators caused by atelectrauma and volutrauma). Dysregulation of the renin-angiotensin system (RAS) is associated with both the development of ARDS and a known mechanism of VILI . Krenn eIzrael et al. tested the treatment effect of human astrocytes therapy (AstroRx) in an endotoxin mouse ARDS model . They showed a significant reduction in multiple inflammatory mediators, improved lung histopathology and reduced mortality in AstroRx treated mice. This study demonstrated the immunosuppressive capacity of AstroRx cells and suggest an innovative ARDS treatment. In addition, this group is currently evaluating the therapeutic role of AstroRx in amyotrophic lateral sclerosis patients.ARDS can cause a massive release of inflammatory mediators often referred to as the “cytokine storm”. This hyperinflammatory response can lead to increase pulmonary microvascular permeability resulting in alveolar flooding with edema, a hallmark of ARDS lung pathology. There is growing evidence that cell-based therapies  have therapeutic efficacy for ARDS . Izrael Mahida et al. developed and in vitro model to assess the impact of ARDS on AMs . Normal AMs were harvested from lobectomy patients and then treated with bronchoalveolar lavage fluid (BALF) collected from ARDS patients. They found that ARDS BALF decreased AMs efferocytosis and Rac1 gene expression, but phagocytosis was not impaired. These findings are similar to that found in AMs from ARDS patients suggesting that this is an effective in vitro model to study the impact of ARDS on AMs. They also found that Rho-associated kinase partially resorted AM efferocytosis.Impaired alveolar macrophage (AM) efferocytosis plays a role in ARDS pathogenesis, , howeverPetit et al. reviewed the pathophysiology of RV function in ARDS and some potential treatments to improve function including ventilator adjustments, prone positioning, nitric oxide (NO) inhalation, and veno-venous ECMO (VV-ECMO) . The impact of ventilator settings on RV failure and acute cor pulmonale was reviewed extensively. It was concluded that ventilator settings should be adjusted to a Pplat <27cmH2O, inspiratory rate increased to reduce PaCO2, limit PEEP level, and optimize O2 delivery not the P/F ratio. They conclude that the RV protective approach should be evaluated in a future RCT with ECMO considered in extreme failure. Integrating the findings from this study to those by Andrews et al. and Rola and Daxon, pulmonary vascular resistance (PVR) is minimal at normal EELV   failure. Clinical options at this point include extracorporeal membrane oxygenation (ECMO) giving the lung more time to heal. apacity) . Thus, aLiu and Dean reviewed the possible use of gene therapy that offers a highly controlled and targeted strategy to treat acute lung injury at the molecular level (Liu and Dean). Topics include delivery stategy, classes of targeted genes, and outcomes on ARDS pathogensis and resolution. They conclude that no combination of genes is responsible for ARDS, although several genes have been targeted up- and downregulation of genes with varying degrees of success. Early studies focused on increasing the expression of ion channels and tranporters to accelerate alveolar edema removal and have had minimal success. Current strategies targeting a reduced inflammatory response and repair or strengthening the alveolar-capillary barrier have shown more promise. Greater emphasis should be placed on studies using more clinically applicable large animal models designed to treat existing disease. The major limitation of effective gene therapy remains optimizing the gene delivery system.Few pharmacological approaches to treat ARDS are available. Villar et al. reviewed the physiologic-based gaps in 14 negative and positive RCTs . Treatment strategies used in these RCTs included adjunct therapies (neuromuscular blockage (NMB) and prone position), optimal PEEP selection, HFOV, ECMO, and immune modulators. The findings from their study were as follows:Ultimately, treatment strategies for ALI and ARDS must be tested in RCTs to identify clinical efficacy. The ACURASYS trial investigated the hypothesis that by eliminating spontaneous breathing using NMB would improve lung mechanics and oxygenation in ARDS patients. However, it was concluded that NMB is not recommended in moderate to severe ARDS since patient-ventilator asynchronies increase. From a physiologic standpoint NMB should be used only if the patient has a ventilator pattern that could result in VILI.Although the PROSEVA trial is controversial, the prone position has been shown to be highly effective as an ARDS treatment. There are 5-mechanisms suggested for the proning-induced improved oxygenation: (i) increased EELV, (ii) changes in regional diaphragm motion, (iii) improve ventilation/perfusion matching, (iv) increased secretion clearance, and (v) the weight of the heart is removed from the lung. A second clinical trial was suggested to confirm the large treatment effect seen in the first RCT.Although there is strong physiologic evidence that heterogeneous lung collapse is a mechanism driving VILI there is currently no consensus on the use of RMs to open the lung nor the method to set PEEP to normalize EELV and stabilize alveoli. The ART and PHARLAP trials showed no benefit of RMs with the ART trial showing an increase in ARDS related 6-months mortality. The EPVent study using esophageal-guided PEEP showed no difference in mortality as compared with the control group. Both studies had numerous design faults and thus with fine tuning both may 1 day improve outcomes but currently neither strategy is recommended.Similar results were found in the EOLIA trial using ECMO vs. a control group which was stopped early. The main problems with the study were the expected 20% absolute risk reduction was unreasonable and 28% of the patients in the control group crossed over to receive ECMO. Also like the above ART and EPVent studies another ECMO RCT was recommended with a lower anticipated absolute risk and no cross over patients.Inflammation causing disruption to both pulmonary endothelium and epithelium resulting in a high permeability pulmonary edema is a hallmark of ARDS pathophysiology. Thus, RCTs to reduced inflammation and edema have been conducted. However, a systematic review showed that there is currently no pharmacologic intervention that could reduce ARDS mortality . The BALThis group concludes that future RCTs must be personalized to subclasses of ARDS patients that are physiologically able to respond to the treatment therapy. In addition, treatment must be personalized to the patient’s specific lung physiology and morphology in order to improve patient outcomes.Beretta et al. computationally modeled ABB disruption taking into account Starling forces, surfactant function, and edema safety factors including: (i) capacity of fluid accumulation on the thick side of the ABB, (ii) increased interstitial pressure, and (iii) increased lymph flow . This extensive review covers the mechanisms of ABB disruption, edema development time constants, factors preventing the development of edema, a “tipping point” in ABB injury followed by rapid alveolar flooding, and the role of spontaneous and mechanical ventilation. This study supports those of Rola and Daxon study (Rola and Daxon) showing that the TCAV™ method to set and adjust the APRV mode would favor reduced edema formation.Inflammation and biotrauma can increase the permeability of air-blood barrier (ABB) resulting in pulmonary edema and plays a major role in both ARDS and VILI pathogenesis. . BerettaThe papers in our Research Topic discuss novel and innovative treatment strategies for the patient with acute lung injury (ALI). Potential breakthrough methods of protective mechanical ventilation are discussed. Although there are currently no pharmacologic therapies for ARDS the recent DEXA-ARDS trial lends hope that pharmacologic interventions may be available in the near future. The mechanisms behind ALI-induced loss of lung fluid balance resulting in edema formation are discussed and analyzed using computational models. This work ties in with novel ventilation strategies that may also reduce edema formation. In addition, the innovative use of gene therapy to remove edema from flooded alveoli is reviewed. Lastly, success or failure of RCTs designed to treat ARDS are analyzed form physiologic basis with the goal to identify which clinical trials should be repeated and how to improve the quality of future RCTs.


While the Canadian universal health system provides access to basic services, key health benefits are employer dependent. Given that non-standard workers (NSWs) only rarely have access to such benefits they have increased vulnerability to the many insecurities derived from their precarious employment, as clearly seen during the pandemic. The growing problem of non-standard work and workers’ heightened risk for health status deterioration, followed by a possible accentuation of health inequities, is a population health concern. This study summarizes several health services gaps experienced by NSWs and discusses policy implications and possible solutions.From January to July 2021, we conducted semi-structured interviews with a purposive sample of 40 NSWs in Ontario, Canada, part of a larger mixed-methods six-country study, including three European countries. The target population consisted of workers aged 25 to 55 who, at the time of the survey, were in non-standard employment or lost their job due to the COVID-19 pandemic.Our findings highlight complex physical and mental health problems and an overall high burden of disease facing NSWs during the pandemic as linked to a combination of constant stress and worry arising from their employment insecurity, the limited and inconsistent income available to cover their basic needs, and the inadequate and unsafe working conditions they are afraid to challenge. Despite their increased health needs, given that specialized health services are not available to them for free they face financial barriers in accessing much needed health services that could help improve their health status and as a result, delay seeking care or avoid it altogether.Sustainable multi sectorial policy solutions are needed including the adoption of relevant labour market legislation and increases in social and health expenditures along with re-adjustments in the ways in which health services are delivered.• During the pandemic non-standard workers in Ontario, Canada experienced complex health problems and, despite increased health needs, encountered barriers in accessing specialized health services.• The growing problem of non-standard work and workers’ heightened risk for health status deterioration, followed by a possible accentuation of health inequities, is a population health concern.


Schizophrenia is a complex mental disorder, which has been recently conceptualized as a neurodevelopmental disease. This conceptualization has changed the psychopathological approach to schizophrenia, which is now described as lying on a continuum from mild psychotic experiences to frank psychotic episodes. According to this theory, the presence of psychotic symptoms would represent the final pathway of a complex dysregulation and interaction of different genetic and environmental risk factors. As regards genetic liability, recent genome-wide association studies have identified a total of 108 loci containing common risk alleles, and which meet genome-wide significance. As regards environmental factors, higher rates of schizophrenia have been found in ethnic minority groups, in persons who are heavy cannabis smokers, in those who suffered from severe childhood traumas, in persons who have been reared in highly deprived settings. The identification of risk factors associated with vulnerability to psychosis is essential for improving our understanding and early detection of vulnerable individuals, and to propose tailored and timely interventions for sufferers. There is the need for an interdisciplinary approach to schizophrenia which includes screening procedures for individuals reporting specific vulnerabilities and treatment strategies tailored on patients’ needs.No significant relationships.


As an example, in recent data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), these classical cardiovascular risk factors explain less than 40% of all of the burden of subclinical atherosclerosis, as measured from the common carotid artery intima-media thickness.Cardiovascular diseases are preventable, but control over the associated risk factors begins with identification of new risk factors beyond the classical ones. Several new risk factors have emerged over the last few years. Changes to thyroid function, such as those due to subclinical thyroid diseases or to alterations in thyrotropin (TSH) and free thyroxine (FT4) levels, are one of these. ,Thyroid diseases have worldwide prevalence, and Brazil is one of the countries with the highest prevalence of thyroid diseases.,,,,In addition to the burden of overt thyroid diseases, subclinical thyroid diseases characterized by low TSH levels with normal FT4 levels  or by high TSH levels with normal FT4 levels  have been recognized over recent years as non-classical risk factors for cardiovascular diseases.Brazil has also contributed to studies on the association of subclinical thyroid diseases with subclinical atherosclerosis. Subclinical hypothyroidism was found to be associated with higher common carotid artery intimal-media thickness values, using euthyroid subjects as the reference , after multivariate adjustment for sociodemographic and cardiovascular risk factors.In ELSA-Brasil, an association between low TSH levels (first quintile) and coronary artery calcium score was observed in the entire sample of men and women, even after multivariate adjustment for sociodemographic and cardiovascular risk factors , using the third quintile as the reference. In an analysis restricted to men, TSH levels in the first quintile were associated with coronary artery calcium (CAC) scores > 100 Agatston units . However, in women, there was a U-shaped curve such that TSH levels in both the first quintile  and in the fifth quintile  were associated with CAC > 100 Agatston units. Subjects with TSH levels within the range of subclinical hyperthyroidism and low-normal values (first quintile) had higher odds for CAC > 100, using the third quintile of TSH levels as the reference.,,,In this setting, it is essential to be able to diagnose occurrences of thyroid diseases in men. Previous Brazilian data showed that diagnoses of thyroid diseases among older men in low socioeconomic strata are made less often than would be expected.This intricate relationship between thyroid and cardiovascular diseases, especially among people of low socioeconomic status in Brazil needs to be investigated more deeply to identify possible strategies for dealing with the problem. Brazil has particular characteristics that may suggest that considerable overlap exists between concomitant occurrences of these two diseases and presence of a high burden from their association in the general Brazilian population. Now is the right time to work on this!


Arrhythmias and sudden cardiac death with sexual activity are rare. However, the demographics are changing regarding the cardiovascular patients at risk for these events. Recent studies have highlighted that the individuals having cardiac events during sexual activity are becoming younger, with a higher proportion of female decedents than previously described. There needs to be an open dialog between the cardiovascular team and the cardiac patient to provide the education and reassurance necessary for cardiovascular patients to participate in sexual intercourse safely. This paper reviews how sexual activity can lead to an increase in cardiac arrhythmias and sudden cardiac arrest in patients that are not medically optimized or are unaware of their underlying cardiac condition. The most common cardiovascular diseases associated with sexually induced arrhythmias and arrest are discussed regarding their potential risk and the psychosocial impact of this risk on these patients. Finally, cardiovascular medications and implantable cardioverter-defibrillators (ICDs) are addressed by reviewing the literature on the safety profile of these cardiac interventions in this patient population. Overall, sexual activity is safe for most cardiac patients, and providing proper education to the patient and their partner can improve the safety profile for patients with higher risk cardiovascular conditions. To give the appropriate education and reassurance necessary, cardiovascular team members need an understanding of the pathophysiology of how sexual activity can provoke arrhythmias and sudden cardiac arrest. Healthcare providers also need to build comfort in speaking to all patients and ensure that sexual partners, female patients, and those in the LGBTQIA + community receive the same access to counseling but tailored to their individual needs. Although it is rare, there is considerable trepidation regarding cardiac arrhythmias and sudden cardiac death with sexual activity. This apprehension is not only present in patients with cardiovascular disease but also patients with no known risk factors for arrhythmias or sudden cardiac death. In a recently published study in JAMA, when reviewing 6,847 sudden cardiac deaths across twenty-six years in London, the risk of death during or within an hour of sex was rare (0.2%). However, this study differed from previous studies due to the lower average age of patients at risk and the higher proportion of female decedents . While tIn 2012, the American Heart Association (AHA) published a scientific statement paper on sexual activity and cardiovascular disease (CVD) , 4. As wPatients and their partners can have various concerns ranging from sexual performance to concerns about exacerbation of their disease process, which can decrease the frequency of sexual activity or lead to the complete cessation of sexual activity due to fear and anxiety. To explore sexual counseling needs, sexual concerns, and sexual activity of patients with heart failure, a survey study of 45 patients showed that the majority (77%) did not discuss sexual concerns with a health care professional. Sexual concerns included erectile problems (74%), partner overprotectiveness (63%), orgasmic difficulties (51%), lack of sexual interest (42%), and partner fear of sex (36%) .The taboo regarding arrhythmias and sudden cardiac death during sex can extend past the patient and their partner and can also impact clinicians. Health care professionals often feel uncomfortable discussing sexual activity with their patients, particularly female patients and those in the LGBTQIA + community. In a small study of women postmyocardial infarction, many resumed sexual activity without guidance from their physicians. And when a discussion was held about resuming sexual activity the patients usually initiated the conversation .This paper reviews the prevalence and physiology of arrhythmias and sudden cardiac death with sexual activity, and the steps healthcare professionals need to take to provide reassurance while maintaining safety in patients at risk for arrhythmias and sudden cardiac death.Arrhythmias induced during sexual activity is postulated to occur due to increased sympathetic activation or ischemia due to increased myocardial oxygen demand related to increased physical activity. Patients with channelopathies and inherited cardiomyopathies are more at risk for arrhythmias due to increased sympathetic activation. Whereas those with ischemic heart disease are at increased risk of arrhythmias due to increased myocardial demand during physical activity.In individuals with channelopathies the pathophysiology on how sympathetic activation precipitates sudden cardiac death varies greatly. In people with Brugada syndrome (BrS) there are multiple theories on the role of the sympathetic nervous system as a potential precipitant of sudden cardiac arrest. These people tend to have reduced cAMP and norepinephrine concentrations found in endomyocardial biopsies, ECG fluctuations with autonomic modulation and a higher incidence of cardiac arrest at night suggesting that cardiac vagal tone may have a significant contribution to arrhythmias in people with BrS . WhereasInherited cardiomyopathies such as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and Hypertrophic Cardiomyopathy (HCM) can have varied risk profiles in regards to sudden cardiac death based on phenotypic expression, predominant genetic mutation and progression of disease over time. ARVC is an inherited cardiomyopathy that is characterized by the fibrofatty infiltration of the right ventricle but can also infiltrate the left ventricle . As thisFinally, ischemic heart disease whether from atherosclerotic heart disease, coronary vasospasm, myocardial bridging or anomalous coronary arteries can cause acute ischemia when there is an increased metabolic demand placed on the heart due to physical activity such as sex which often manifests as chest pain but can rarely present as ventricular fibrillation or polymorphic ventricular tachycardia.Sexual activity is considered to require a low to moderate metabolic equivalent of task (MET), but even mild physical activity in a de-conditioned patient with cardiovascular disease while trying to achieve an orgasm during coitus can precipitate arrhythmias or sudden cardiac death .When counseling cardiovascular patients, prior to the patient participating in sexual activity, the clinician should ensure that the patient can perform between three to five METs of activity without symptoms. This number is derived from a trial measuring metabolic expenditure in 10 healthy married couples aged 25–43 engaged in foreplay to orgasm and performing various sexual activities and positions during coital and non-coital stimulation by their partner or through self-stimulation . If the Most patients with cardiovascular disease can have sex safely without clinical arrhythmias or sudden cardiac death. Even in patients with a known diagnosis of supraventricular tachyarrhythmias, sexual activity is safe and reasonable in well-controlled patients . DespiteArrhythmias associated with ischemic heart disease include supraventricular arrhythmias  and sudden cardiac death due to ventricular tachycardia and fibrillation. Patients with ischemic heart disease often receive counseling about safely resuming sexual activity to prevent recurrent angina or myocardial infarction; although counseling regarding arrhythmias and the importance of bystander cardiopulmonary resuscitation (CPR) for their partner, while important, is rarely provided. Although sex-associated death is rare and nearly universally witnessed, there is almost a five-fold lower survival rate due to the low rate of bystander CPR . EducatiPatients with ischemic heart disease should also be counseled on using recreational sexual enhancers due to their ability to potentiate arrhythmias. Arrhythmias and sudden cardiac death can also occur in patients with non-ischemic structural heart disease or structurally normal hearts, such as those with channelopathies and other inherited cardiovascular syndromes. Non-ischemic structural heart diseases, such as Hypertrophic Cardiomyopathy (HCM), Arrhythmogenic Ventricular Cardiomyopathy (AVC), idiopathic fibrosis, and aortic dissection have been described through registry data and case reports . The risIn a recent study by Finocchiaro, sex-associated sudden cardiac death was rare and occurred in 17 out of 6,847 cases (0.2%), with 8 of these patients having non-ischemic structural heart disease . OverallLong QT Syndrome (LQTS) and Catecholaminergic Polymorphic Ventricular Tachycardiac (CPVT) are channelopathies that can lead to arrhythmias such as torsade de pointes (TdP) or polymorphic ventricular tachycardia (PMVT) which can deteriorate into ventricular fibrillation. In an electronic medical review of patients seen by the Genetic Heart Rhythm Clinic, sex-induced cardiac events were more likely in CPVT than in LQTS. Sex-induced cardiac events occurred in two out of forty-three patients (4.7%) with CPVT but in none of the patients with LQTS . DespiteICDs are implanted in patients as either primary or secondary prevention of life-threatening arrhythmias (ventricular tachycardia and fibrillation). Although ICDs are life-saving devices for at-risk patients, receiving a shock during sexual activity or fear that their partner might receive an ICD shock is a frequent concern of patients and their partners. It causes significant anxiety and fear of sexual activity , 24. CouOptimizing patients so that they can perform three to five METs so that they can participate in sexual activity can be achieved through cardiac rehab. A recent meta-analysis of fourteen trials showed that cardiac rehabilitation could improve sexual function . In addiCardiovascular medications can cause erectile dysfunction, decreased sex drive, and decreased vaginal lubrication due to their mechanism of action and the nocebo effect , 27. ThiCounseling, education, and shared decision-making can improve patient adherence to cardiac medications. If the patient continues to have significant issues regarding sex drive, erectile dysfunction, or vaginal dryness, alternate but equivalent medications can be prescribed. For patients with cardiovascular disease and erectile dysfunction, phosphodiesterase type 5 inhibitors can be prescribed in patients not taking long-acting nitrates. Vaginal dryness can be safely treated with topical estrogens to decrease pain with sexual intercourse , 27. FinSex is a salient part of life and procreation that contributes to overall wellness and quality of life. In most individuals, sex can occur safely without risk of death or arrhythmias. But it is devastating when arrhythmias or sudden cardiac death do occur during sexual activity. Patients and their partners should be given reassurance that sex is reasonable and safe in most situations. However, they should also receive personalized counseling and education on the likelihood of arrhythmias or sudden cardiac death as it applies to their disease process and how to minimize these events with medication adherence, avoiding non-FDA-approved sexual enhancers, and the importance of bystander CPR.Medical providers can improve outcomes in patients at risk for arrhythmias and sudden cardiac death by initiating a conversation about sexual activity with their at-risk patients. During these counseling sessions, the provider should listen to the patient’s concerns regarding sexual activity and make shared decisions regarding cardiovascular medications and devices while abiding by current medical guidelines. Cardiovascular specialists can help stratify patients at risk for arrhythmias and sudden cardiac death by utilizing exercise stress tests and improve outcomes by enrolling patients in cardiac rehabilitation to improve aerobic conditioning when appropriate. Health care professionals also need to be aware of potential disparities in healthcare and ensure that sexual partners, female patients, and those in the LGBTQIA + community receive the same access to counseling but tailored to their individual needs.CD and AV created the outline, wrote sections, and edited the entire manuscript. CD created


We are pleased to respond to Noriyuki Yamato and Tatsuya Fujikawa for their comments on our recent study about the effects of temperature changes between neighboring days (TCN) on acute aortic dissection (AAD) in non-heating periods.central heating may be a modifier for temperature-related AAD risk and burden”, but not stated “central heating reduces risks of AAD”. In the discussion section, we suggested potential protective effect of central heating as one of the possible explanations for the differential effects of TCN on AAD in heating and non-heating period. Although the differential effects might be not only due to central heating, but also related to other factors, the potentially critical role of indoor heating cannot be overlooked. Second, there seems to be some misunderstanding by Yamato and Fujikawa on the effect of TCN in winter. It is not like they stated that “negative TCN did not significantly increase relative AAD risk”, negative TCN in fact significantly increases relative AAD risk in the linear function (Table 1), and the exposure-response curve in Figure 4e also presents a marginally significant association in winter in cities without central heating. We acknowledge that in cities without central heating, the association between negative TCN and AAD is weaker in magnitude in winter than in other seasons. The lower risk observed in winter suggests that some personal protective procedures might also play a role in mitigating the harmful effect of negative TCN. Of note, although central heating is not provided in cities without central heating in China, personal protective procedures such as air conditioning and underfloor heating are widely used in winter in these cities.Yamato and Fujikawa suggest that it is debatable whether central heating reduces risks of AAD induced by negative TCN, because they think negative TCN does not significantly increase relative AAD risk not only in heating periods in cities with central heating, but also in winter in cities without central heating. First, the role of central heating seems to be over-interpreted by Yamato and Fujikawa. In fact, we just objectively presented the finding that “As Yamato and Fujikawa mentioned, we found there is an association between increased AAD onset and negative TCN in cities with central heating. Exactly because the significant association in non-heating periods and the non-significant association in heating period, we assumed that central heating might modify the association between TCN and AAD onset. Nevertheless, we have never stated that the significant association occurred during non-heating period is an effect of central heating.,,Another concern Yamato and Fujikawa raised is whether sudden drops in temperature are associated with increased AAD onset during non-heating seasons. The independent effects of negative TCN on cardiovascular diseases have been widely reported in previous studies.same hour of day, thus the circadian rhythms can be automatically controlled.We agree with Yamato and Fujikawa that the summer increases in nighttime blood pressure might not be due to temperature. However, summer increases in nighttime blood pressure only present the circadian rhythms of the blood pressure, but not the association between temperature and blood pressure. Our focus is the association between temperature and blood pressure for a person in the same calendar year, month, day of week, and Therefore, we think TCN is independently associated with AAD onset but not just a confounding factor in non-heating period in the current study. Because TCN might also be a confounding factor in the association between temperature and AAD onset, we have controlled for TCN in the main analyses.We declare no competing interests.