Monkeypox 2022 exhibits unprecedented human-to-human transmission and presents with different clinical features than those observed in prior outbreaks. Previously endemic only to West and Central Africa, the monkeypox virus spread rapidly world-wide following confirmation of a case in the United Kingdom on May 7, 2022 of an individual that had traveled to Nigeria. Detection of cases with no travel history confirms on-going community spread. Emergency Medical Services (EMS) professionals will likely encounter patients suspected or confirmed to have monkeypox, previously a rare disease and therefore unfamiliar to most clinicians. Consequently, it is critical for EMS medical directors to immediately implement policies and procedures for EMS teams – including emergency medical dispatchers – to identify potential monkeypox cases. These must include direction on actions EMS professionals should take to protect themselves and others from virus transmission. Monkeypox 2022 may manifest more subtly than it has historically. Presentations include a subclinical prodrome and less dramatic skin lesions – potentially limited to genital or anal body regions – which can be easily confused with dermatologic manifestations of common sexually transmitted infections (STIs). While most readily spread by close contact with infectious skin lesions on a patient, it is also transmissible from fomites, such as bed sheets. Additionally, droplet transmission can occur, and the virus can be spread by aerosolization under certain conditions. The long incubation period could have profound negative consequences on EMS staffing if clinicians are exposed to monkeypox. This report summarizes crucial information needed for EMS professionals to understand and manage the monkeypox 2022 outbreak. It presents an innovative Identify-Isolate-Inform (3I) Tool for use by EMS policymakers, educators, and clinicians on the frontlines who may encounter monkeypox patients. Patients are identified as potentially exposed or infected after an initial assessment of risk factors with associated signs and symptoms. Prehospital workers must immediately don personal protective equipment (PPE) and isolate infectious patients. Also, EMS professionals must report exposures to their agency infection control officer and alert health authorities for non-transported patients. Prehospital professionals play a crucial role in emerging and re-emerging infectious disease mitigation. The monkeypox 2022 3I Tool includes knowledge essential for all clinicians, plus specific information to guide critical actions in the prehospital environment. Sustained human-to-human and community transmission are well-documented. Phylogenetic data indicate that the monkeypox virus in the 2022 outbreak has acquired significant mutations, which may account for its increased human-to-human transmission and altered clinical features. Human monkeypox has likely been circulating as a cross-continent, cryptic human transmission for some time; however, the first 2022 case outside of Africa was confirmed in the United Kingdom on May 7th in an individual with a history of travel to Nigeria. Case numbers precipitously increased in subsequent days, and epidemiological data revealed that many cases were not associated with travel to endemic regions.On July 23, 2022, the World Health Organization  declared the monkeypox 2022 outbreak the seventh-ever Public Health Emergency of International Concern (PHEIC). Monkeypox 2022 is a viral illness whose transmission rate and clinical features have shifted, enabling it to produce an unprecedented, rapidly expanding outbreak in non-endemic regions world-wide. Patients in the 2022 outbreak frequently present with non-classical signs and symptoms. While monkeypox may not be as easily transmissible as coronavirus disease 2019 (COVID-19), the escalating outbreak is a public health emergency and can lead to reverse zoonosis with the creation of new endemic areas, recurrent outbreaks, and negative effects on health care staffing. In addition, if containment measures are not immediately implemented, there is a high risk of the virus swiftly moving into vulnerable populations, such as children, pregnant women, the elderly, and the immunocompromised, leading to higher morbidity and mortality. As of July 2022, limited testing capacity and vaccine supply contribute to this concern.As of July 25, 2022, confirmed cases rose to 17,156 in at least 69 non-endemic countries.This research report provides a concise summary of current knowledge about monkeypox and a novel Identify-Isolate-Inform (3I) Tool Figure  for use  The incubation period ranges from five to 21 days . The first signs and symptoms are constitutional and called a prodrome because they manifest before the rash. These include influenza-like illness ; lymphadenopathy ; and enanthem, often in the mouth and anus. Prodromal signs and symptoms typically precede the exanthem (rash) by one to four days. While the route of infection can influence clinical manifestations, initial skin lesions in human and non-human primates often present in the anogenital region and then appear on the face, palms, and soles before spreading centrifugally. Skin lesions progress through macular, papular, vesicular (blister), and pustular stages, followed by scabbing and healing. In addition, lesions present in the same stage of development in a given body region. Long-term sequelae of monkeypox infection can include disfiguring scars and permanent blindness resulting from corneal lesions.Classically, monkeypox patients present with signs and symptoms resembling smallpox, a disease declared “globally eradicated” by the WHO in 1980.Unlike the classical monkeypox presentation, cases from the 2022 outbreak may not begin with a prodrome, skin lesions tend to be subdued, and lesions in a given body region may be at various stages of development. Furthermore, the constitutional symptoms can manifest simultaneously with the rash and enanthem. Moreover, lymphadenopathy and lesions on the palms and soles are less common. Hence, these features may have limited utility for differentiating monkeypox from other diseases. Monkeypox can appear similar to numerous more common diseases. The differential diagnosis of monkeypox is broad  can result in transmission to health care workers and others. Persons with confirmed monkeypox can mitigate transmission risk by covering infectious lesions, wearing a mask, and isolating themselves during the contagious period. Once lesions have healed, which can take two to four weeks or longer, they cease to be a source of infection.Prehospital workers may be the first health care professionals to encounter suspected or confirmed monkeypox patients. Clinicians must learn to recognize the risk factors and presentations and consider monkeypox as a possible diagnosis. They should also take special precautions to prevent disease transmission and ensure the effective transfer of care at the receiving facility. More comprehensive data on the history, background, presentation, and management of monkeypox 2022 and the 3I concept are available. Figure  with specific considerations for EMS professionals.The 3I framework was conceived in 2014 during the 2013-2016 Ebola virus outbreak when several Ebola cases presented at hospitals in the United States. The framework is designed to give clinicians high-level, actionable guidance for properly managing infectious diseases and has been applied to at least ten other conditions.Requesting the patient to mask and come to the door of the residence, bringing medications, if possible ;If first responders must go inside to evaluate a patient, first send in a scout paramedic wearing full personal protective equipment (PPE);Apply a surgical mask to the patient for source control (if tolerated); andAvoid aerosol-generating procedures (AGPs).Work is on-going to ascertain whether suspected or confirmed monkeypox patients can be identified at the emergency medical dispatch level. While travel history remains important in determining disease exposure risk, documented community spread in non-endemic regions has limited its usefulness. After emergency medical dispatchers identify a person with suspected or confirmed monkeypox, EMS professionals are advised to implement appropriate infection prevention measures before patient contact. These are similar to those applied during the COVID-19 pandemic and may include:If monkeypox is suspected, prehospital professionals should determine the patient’s likelihood of having the disease based on signs and symptoms and exposure risk. Cases in the 2022 outbreak are less likely to present with classical clinical indicators Figure . Exposur and shoe covers, if available. Notably, PPE used during the COVID-19 pandemic is sufficient to protect prehospital professionals from monkeypox. Source-control measures, including placing a surgical mask on the patient and covering exposed lesions, can lessen the risk of transmission in enclosed spaces . Similarly, avoid AGPs whenever possible because of the increased exposure risk and potential for infectious monkeypox virus aerosols to linger for extended periods in enclosed spaces.Prehospital clinicians should don appropriate PPE throughout first contact, transport, care transfer, and during disinfection of the transport vehicle. Proper PPE includes an N95 respirator/equivalent (or higher), gloves, gown, eye protection,It is imperative that transporting crews relay the patient’s suspected or confirmed monkeypox status to the receiving facility early to allow time for the hospital to prepare and minimize risks of infection spread and delays in the transfer of care. Local or state protocols may require prehospital clinicians to report communicable infectious diseases to their agency’s infection-control officer or health authority, especially for patients not transported to a hospital. Follow required protocols when reporting communicable diseases and health care worker exposures.This research report discusses considerations for the management of suspected or confirmed monkeypox 2022 in the prehospital setting. As of July 11, 2022, a literature search of the PubMed ; MEDLINE ; CINAHL ; and Scopus  databases did not identify any published articles specifically addressing EMS considerations for monkeypox. Given the rapidly evolving nature of the 2022 outbreak, only limited data are available describing the clinical presentation, management, epidemiology, and long-term outcomes. Furthermore, the diagnosis cannot be confirmed in the prehospital setting. Despite this, applying the Monkeypox 3I Tool for EMS Professionals (Figure As demonstrated by the COVID-19 pandemic, prehospital clinicians play a critical role in the management of public health emergencies. Throughout the pandemic, prehospital professionals have assisted with out-of-hospital treatments, vaccination campaigns, and patient transport, among other activities. Although monkeypox 2022 is unlikely to cause a global pandemic on the scale of COVID-19, it is nevertheless a major international public health threat. Prehospital clinicians can apply their unique training and role as the interface between at-risk patient populations and health care to mitigate the further spread of monkeypox 2022. Importantly, before this outbreak, monkeypox was very rare; thus, most health care workers have never encountered the disease. Expansion of cases to non-endemic regions creates a risk of reverse zoonosis and the creation of new endemic zones across the globe.Monkeypox 2022 represents a rapidly escalating outbreak with extensive and sustained global human-to-human and community transmission. Cases in the 2022 outbreak differ from classical clinical presentations as described in endemic regions of Central and West Africa and during the 2003 zoonotic monkeypox outbreak in the United States.identify and isolate such patients to protect themselves and other health care workers from exposure and inform the relevant health authorities to help mitigate the spread of this re-emerging infectious disease.Prehospital clinicians play a key role in infectious disease mitigation, as demonstrated by the COVID-19 pandemic. The science on the monkeypox 2022 outbreak continues to evolve. It is imperative that clinicians, particularly those in the prehospital setting who may encounter suspected or confirmed cases, immediately


Spatial navigation is a complex cognitive function that declines in older age. Finding one’s way around in familiar and new environments is crucial to live and function independently. However, the current literature illustrates the efficacy of spatial navigation interventions in rehabilitative contexts such as pathological aging and traumatic injury, but an overview of existing training studies for healthy older adults is missing. This scoping review aims to identify current evidence on existing spatial navigation interventions in healthy older adults and analyze their efficacy.To identify spatial navigation interventions and assessments and investigate their effectiveness, four electronic databases were searched . Two independent reviewers conducted a screening of title, abstract and full-texts and performed a quality assessment. Studies were eligible if (1) published in English, (2) the full text was accessible, (3) at least one group of healthy older adults was included with (4) mean age of 65 years or older, (5) three or more spatial navigation-related training sessions were conducted and (6) at least one spatial ability outcome was reported.N = 1,003, age-range 20–95 years, 51.5% female), only healthy older adults  were assessed further. Studies differed in sample size (n = 22–401), type of training, total intervention duration (100 min–50 h), and intervention period (1–16 weeks).Ten studies were included .This scoping review was preregistered at Open Science Framework ( Many older adults perceive an autonomous and meaningful life within their community as a desirable goal and strive to live independently as long as possible . This isWhether older persons are able to live and function independently on a daily basis is therefore determined by finding their way around familiar and new environments, the ability to move outdoors, as well as adequate physical, cognitive, and mental health . The steThis decline can cause fear of not finding a particular destination like the way home, or even getting lost . To reacNext, to the individuals’ cognitive and physical conditions, precursors of smaller life-spaces appear to be disadvantageous neighborhood properties, transportation issues, and lower levels of education and income . A largeNumerous studies have investigated the training of spatial navigation abilities within pathologic populations to facilitate autonomy. A variety of different training strategies like augmented or virtual reality training, behavioral techniques, route and landmark learning, and combinations with motor-cognitive training approaches yielded very promising results .Despite these encouraging findings, little research has explored so far whether and how spatial navigation can be trained in a healthy older population. Closing this research gap is crucial, as effective training methods could impact significantly how healthy older adults keep up an independent life for as long as possible. This includes maintaining higher levels of physical and cognitive performance, living autonomously, remaining in familiar surroundings, having the possibility for social support and participation, having lower mental health incidences, and higher satisfaction with life, thereby taking a load off the health care system.Thus, aiming to summarize previous and to facilitate future research in this field, this scoping review systematically reports the current knowledge about intervention studies addressing spatial navigation in healthy older adults. Furthermore, this scoping review provides the applied intervention characteristics and spatial ability-related outcome measures to address the following questions:Which interventions for healthy older adults can be identified targeting spatial navigation abilities?What spatial ability-related assessments were used in those studies to evaluate the effectiveness of the respective spatial interventions for healthy older adults?Which effects of spatial navigation interventions for healthy older adults were observed on spatial abilities?Relevant literature was identified by systematically searching the electronic databases Pubmed, Web of Science, CINAHL, and EMBASE. Systematic searches were conducted from the inception of the respective database up until September 2021. The search strategy was developed and refined according to the PICOS scheme , advised by a librarian. All search results were exported into Mendeley (version 1803). After the removal of duplicates, the remaining citations were uploaded to Rayyan QCRI , a free-Both reviewers documented their data charting process with a modified version of the ‘Data collection form for intervention reviews: RCTs and non-RCTs’. Applied items were key study characteristics like the author(s), year of publication, study design, the aim of the study, population characteristics, intervention characteristics, control interventions, follow-ups, drop-outs, assessed outcomes, and self-reported limitations.Additionally, information was collected about the content of spatial navigation interventions, training modalities, spatial ability-related outcome measures and outcomes. It should be noted, that only behavioral spatial ability-related outcome measures are reported and discussed, disregarding additional reported data . Data were listed as a mean and standard deviation (SD) if reported. To capture all relevant information, the form was refined in an iterative process and data were updated continuously. Extracted data of both researchers were compared and discrepancies were resolved by discussion. According to the research questions, data about study design, study aim, population and intervention characteristics, spatial ability-related outcome measures and outcomes were used to identify relevant studies and to summarize the applied spatial ability-related assessments and training effects on spatial navigation abilities.Included studies met the following criteria: (I) published in the English language, (II) accessible as a full-text version, (III) at least one group of healthy older adults included with a (IV) mean age of 65 years or older, (V) three or more spatial navigation training sessions conducted and (VI) at least one spatial ability-related outcome reported.Studies were excluded if they were (I) only cross-sectional or (II) books, reviews, editorials, single case studies, conference abstracts, or interviews. A sample of solely (III) pathologically impaired participants also led to exclusion as well as (IV) the absence of spatial outcomes.cf. criteria 1–11 in A quality assessment was performed according to As shown in cf.Summarizing all records, a total of 1,003 adults participated in the studies cf., this inStudies included in this systematic scoping review used heterogeneous designs and differed significantly in methodological quality . Six stuN = 10) differed in the interventions provided as well as the training methods  showed changes from pre-to posttest.The aim of this scoping review was to outline the current body of evidence on spatial navigation interventions for healthy older adults to increase spatial abilities. In addition, the intervention characteristics, applied spatial ability-related outcome measures, and results were summarized to describe relevant training effects of spatial ability training in healthy older adults. A scoping review of the literature was selected as approach to map out a wide-ranging picture of the available research in this field while still maintaining methodological rigor and diminishing bias .A total number of 10 studies met the applied inclusion criteria and were subjected to a quality assessment. The quality of the included studies was moderate to high. Trials included a total number of 1,003 participants, 368 of those being healthy older adults and therefore target group of this scoping review. Overall, the study outcomes indicate that spatial abilities can be improved in healthy older adults by means of the designed training interventions. Six of nine studies reporting pre-post data found significant improvements for at least one of their spatial ability-related outcomes , howeverThe first aim of this scoping review was to summarize the characteristics of existing spatial navigation interventions to enhance spatial abilities in healthy older adults. A total number of 10 different interventions could be identified. Overall, the implemented training methods varied widely, active and passive movement approaches in virtual environments  were useThis variety continued for the applied training periods (1–16 weeks), the overall training duration (100 min–50 h) and the duration of training sessions (20–60 min).From an exercise science point of view, the effect of cognitive-motor interventions is highly dependent on the training control and the conduction of the training load  addressing cognitive functions  to task-specific tests  and spatial ability-related questionnaires. Six of the included studies applied standardized tests , while tThe studies performing cognitive training interventions using realistic scenarios  or task-This overview depicts a broad variety of applied spatial ability-related outcome measures in relation to the different intervention approaches. The applied assessments depict partial aspects of the complex cognitive ability called spatial navigation, which needs to be considered when interpreting outcomes in terms of intervention effects. The majority of assessments capture small-scale spatial abilities only, which mainly cover two-and three-dimensional spatial visualization and spatial relations. Few of the used assessments survey large-scale spatial abilities, which refer to the concrete ability to orientate and navigate in complex large-scale environments .This does not allow for drawing conclusions on the eligibility of selected spatial ability-related outcome measures. Overall, it can be assumed that lab-based, standardized assessments of spatial abilities are suitable tools in basic research as they can depict specific cognitive aspects. At the same time, task-specific large-scale assessments might be more suitable to observe intervention effects since they illustrate the complex aspects of spatial navigation performance rather than underlying cognitive mechanisms. Furthermore, these tools could also be considered to reflect the transfer of the measured spatial ability to everyday spatial navigation more accurately.d and found a range from 0.1 up to 1.3, reflecting small to large intervention effects for the spatial measures  in healthy older adults, future research into specific spatial navigation interventions might be a valuable contribution to health prevention and thus not only improve the independence and quality of life in older persons but also take some of the load off the health care systems.Overall, this scoping review revealed open aspects that should be addressed in future training studies. These are (a) studies have to provide a clear definition of spatial navigation and the involved cognitive processes that are addressed in the training, (b) future studies should report effect sizes for the effect of the training intervention to enable a cross-study evaluation (c) future studies should address the positive benefits of the specific training regimes on near and far transfer of underlying spatial cognitive abilities and (d) future studies should investigate the transfer of positive effects of training to daily activities and real-life navigation.Future research should focus on reproducing and extending the available approaches. This could for example imply approaches like the comparison of different types of interventions  to identify the most promising training approaches. Additionally, the comparison of different training modalities could be beneficial to reveal efficient ways to yield improvements following established training principles. The assessment of life space-mobility may be a valuable addition to depict far transfer achievements of spatial ability training in everyday life.MF and CM wrote the first draft of the manuscript. MF, CM, AW, C-PJ, TM, KG, and BW have been involved in the drafting and contributed significantly to the revision of this manuscript. All authors contributed to the article and approved the submitted version.We acknowledge support by the German Research Foundation and the Open Access Publication Fund of TU Berlin.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.


Editorial on the Research TopicSurgical selection of sublobar resection and scope of lymph node dissection for early-stage lung cancerThe standard treatment for non‒small cell lung cancer (NSCLC) includes lobectomy, pneumonectomy, and sublobar resection. In selecting the surgical method, doctors need a safer, less invasive method that can be done more rapidly and provide the most suitable type of resection at different stages of NSCLC. Sublobar resection  can treat smaller lesions and offers better recovery of postoperative pulmonary function. In early-stage lung cancer in patients who are physically fit and have good lung function, there seems to be no difference in perioperative mortality and morbidity rates for lobar or sublobar resection . TherefoLymph node dissection, especially more extensive regional dissection, is thought to improve survival rates in patients with early-stage lung cancer . It is oThe preoperative evaluation of benign and malignant pulmonary nodules in early-stage cancer plays a significant role in the selection of surgical method and prognosis of patients. Common evaluation methods include imaging, gene detection, and tumor-related marker detection. Ye et al.  conducteIn addition, multivariable logistic regression models with backward selection based on the Akaike information criterion were used to identify independent predictors. Xia et al.  retrospePreoperative chemotherapy is commonly used in patients with advanced NSCLC. However, interestingly, for early-stage (stage I) small cell lung cancer, Ye et al.  recommenThe lymph node metastasis of lung cancer is an important reason for the disease’s high mortality rate, so lymph node dissection and exploration in sublobar resection of early NSCLC is very important. Gossot et al.  proposed


Most existing evidence about the prevalence of prenatal cannabis use relies on self-reported measures, which is limited by social desirability bias and recall bias. To date, several studies have examined the validity of self-reported measures of prenatal cannabis use, but this evidence has yet to be synthesized. To address this gap, we performed a scoping review to systematically identify and synthesize existing evidence on the validity of self-reported measures of cannabis use among pregnant women.We searched PubMed, PyschINFO, CINAHL, Cochrane/CENTRAL, and Google Scholar for peer-reviewed studies published in English between January 2010 and June 2021. We included studies that compared self-reported measures of cannabis use to a biochemical measure of cannabis  in pregnant women. We excluded studies reporting solely on prenatal cannabis use prevalence as well as those that examined self-reported drug use in which cannabis use was not a distinct category.We found 12 unique studies (11 primary studies and one systematic review) that examined the validity of self-reported prenatal cannabis use, compared to a biochemical sample. Most studies were conducted in the US and conducted in either a hospital or clinical setting. We found that self-report was more valid in populations with a current or prior history of drug use. Self-report was also more valid when assessed via interviews by research team members than health care provider screenings or self-administered surveys. The most commonly used biochemical measure used was urine drug testing, which was found to have the highest level of concordance with self-report.This scoping review systematically mapped existing evidence on the validity of self-reported prenatal cannabis use. Although much remains unknown in this area, an important next step is a systematic review that would provide robust evidence on clinical utilization of self-reported use in conjunction with biochemical samples. Further research is needed to examine validity by type of measure and mode of administration. Additionally, future studies could assess factors associated with disclosure of use across different critical maternal health periods beyond pregnancy.The online version contains supplementary material available at 10.1186/s12884-022-04677-0. Substantial increases in cannabis use prevalence among women of reproductive age over the past decade is a global public health concern –4. Of paEmerging evidence indicates prenatal cannabis use and exposure is not without consequence. Indeed, a recent systematic review and meta-analysis by Marchand et al. found that in-utero cannabis exposure was associated with an increased risk of several adverse neonatal health outcomes compared with infants not exposed . NeonateEffective screening for cannabis use during pregnancy is essential for prevention of adverse perinatal consequences associated with in-utero cannabis exposure. However, most studies reporting on prenatal cannabis use rely on maternal self-report , 14–16. To fill this evidence gap, we performed a scoping review that systematically identified and synthesized existing evidence on the validity of self-reported measures of prenatal cannabis use in comparison to estimates from biochemical samples. In conducting this scoping review, we also aimed to determine if there was enough available evidence on this topic to perform a future systematic review and identify potential questions that could be answered with existing evidence.We aligned this scoping review with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist  or estimates of prevalence from biochemical samples, as comparison between self-report and a biochemical measure was not possible.We systematically searched PubMed, PyschINFO, CINAHL, and Cochrane/CENTRAL from January 2010 to June 2021. We also included the first 200 results from Google Scholar, when sorted via relevance ranking. Given the shifting landscape of prenatal cannabis use, we limited our search from 2010 onward to identify contemporary measures of self-reported cannabis use, as opposed to dated measures that included cannabis in a category with other illicit substances . We developed unique search strategies for each database, which we then piloted. After the initial pilot searches, we adapted the initial search terms to exclude those that did not yield relevant results, which included the following search terms: “survey”, “weed”, and “CBD”. We developed the final search strategy . As the first step of our review process, we exported all search results from each database into EndNote . Next, we imported citations from EndNote  into Covidence. As part of this import process, Covidence automatically de-duplicated citations based on a match of the citation title, author, and date.After search results were imported into Covidence, we performed a two-stage review process in which we screened references for inclusion based on eligibility criteria. To ensure reviewer agreement, two reviewers (KS and ED) piloted the screening process with 25 citations. Inter-rater agreement was high (95%) and thus formal screening began. Then, two members of the research team performed title and abstract screening independently. Upon completion of title and abstract screening, two reviewers screened remaining studies in their full-text, PDF form. Only articles meeting all inclusion criteria moved forward for data extraction. We resolved disagreements between reviewers at any stage using consensus and discussion. Lastly, we performed forward and backward citation searches for the final list of included studies.Two reviewers independently performed data extraction for each included study using modifiable templates in Covidence. We abstracted the following datapoints from each study: study details , population and sample size, study design and methods, details about measures used , outcomes, limitations, recommendations (both for practice and research), and conclusions. Specific outcomes of interest included negative predictive value (NPV), positive predictive value (PPV), sensitivity, specificity, and percent agreement between maternal self-report and biochemical sampling. However, due to expected variation in reporting of outcomes, we included studies that reported other outcomes measuring the relation between maternal self-report and biochemical tests.We performed a narrative synthesis, mapping existing evidence across key categories, including type of biochemical sample used for comparison of self-report and type of self-report used . We also present data in tabular form by country and a separate table reporting recommendations for both future research and practice.After de-duplication, we screened a total of 927 unique articles, resulting in 12 articles included in this scoping review. We detail the study screening and selection process in accordance with PRISMA guidelines in Fig. We report key characteristics of included studies in Table n = 8) compared maternal self-reported prenatal cannabis use prevalence to urine [Most included studies  was the only included study that examined maternal self-report prevalence to meconium samples . In thisTwo studies relied on health care provider verbal screening for self-reported cannabis use. Chang et al. (2017) recorded first obstetric visits for assessment of disclosure of cannabis use via health care provider verbal screening and found that 74% of patients who tested positive for cannabis did not disclose use . AnotherA total of 5 studies utilized structured or semi-structured interviews to assess self-reported cannabis use , 33–36 aThree studies used a written survey to assess self-reported cannabis use , 23, 32.Included studies had numerous recommendations for both future research and practice on this topic Table . SeveralIn this scoping review, we identified and synthesized contemporary evidence on the validity of maternal self-reported cannabis use during pregnancy. We found 12 studies that examined the validity of self-reported prenatal cannabis use in comparison to a biochemical estimate. Most studies were conducted in the US and conducted in either a hospital or clinical setting. The most commonly used biochemical measure used was urine testing, which leaves substantial gaps relating to the evidence on validity of self-report compared to other biochemical measures, such as hair, meconium, or umbilical cord sampling. Given the potential adverse maternal and child health effects of prenatal cannabis exposure, our findings necessitate additional research examining validity of self-reported prenatal cannabis use.Accurate identification of women who use cannabis during pregnancy is imperative for prenatal care providers so that discussions about use and referral to treatment, if necessary, can occur. Undoubtedly, this cannot occur without utilization of valid measures of prenatal cannabis use. However, in our review, we found that self-report of prenatal cannabis use was largely unreliable. Consistent with prior studies, we found that biometric estimates found higher prevalence of prenatal cannabis use compared to self-report. Although biometric estimates of prenatal cannabis use are more resource and time-intensive compared to self-report measures , severalPrior research has shown that ACASI approaches have been associated with increased disclosure of substance use , 42. HowWe found several evidence gaps, which future research should work to address. As there was only one review that examined maternal self-report to meconium samples , we founWhat is the validity and reliability of self-reported cannabis use during pregnancy?;How is the accuracy of biochemical estimates of cannabis use impacted by cannabinoid pharmacokinetics variability and metabolite detection methods ?;How does accuracy of self-reported cannabis use during pregnancy vary across environmental factors ?;What is the extent to which validity of self-reported cannabis use varies as a function of time between collection of self-reported and biochemical samples?;What potential harms or adverse outcomes exist for screening of prenatal cannabis use ? How do these harms or adverse outcomes vary across cannabis policies?To meet the aims of this study, we determined a scoping review, as opposed to a systematic review, was the best approach for several reasons. First, scoping reviews are used to determine the breadth and depth of existing evidence on a topic through systematic identification and mapping of available evidence , 27. SecThere are a few limitations of this scoping review. First, we excluded studies not published in English, which likely resulted in failure to identify all potentially relevant studies. Second, we utilized date restrictions to capture recent studies with contemporary relevancy . However, by using date restrictions in the search, we may have missed in-press or recently published articles yet to be indexed. Among included studies, there was inconsistency in the reported measure for agreement, with some studies reporting agreement in the form of Cohen’s kappa and others reporting sensitivity or specificity. A future systematic review can aim to address this limitation by calculating a consistent measure of agreement across studies for comparison. Another important piece to consider when comparing biochemical estimates in comparison to self-report is the window of time between collection of the two measures. This was beyond the scope of this review but is an important question to answer in a systematic review with possible meta-analysis. Lastly, the small number of studies that used meconium or umbilical cord sampling precluded a proper synthesis of studies for those measures.We conducted a scoping review to identify and map available evidence on the validity of self-reported prenatal cannabis use. We found validity of self-report was poor in comparison to biochemical estimates. Further research is urgently needed to understand and examine factors associated with the validity of self-reported prenatal cannabis use, as well as to develop valid measures of self-reported use. Additionally, a systematic review is urgently needed to guide clinical practice and policy. Until this necessary research can be conducted, clinicians should use the recommendations of prior studies as outlined above.Additional file 1.Additional file 2.


While opioids remain our most potent analgesics in the management of pain, the many potential harms of prescription opioids have become increasingly clear. Despite the analgesic benefits for people with acute and chronic pain , opioid In a prior review , we descPsychological or mind-body interventions have historically been included as part of multidisciplinary treatment for chronic pain and are designed to reduce pain intensity, psychological distress, and pain-related disability. Mind-body interventions (MBIs) confer their benefits via multiple mechanisms, some of which are physiological in nature. For example, MBIs have been shown to positively affect heart rate variability (HRV) in chronic pain patients, which is important as chronic pain has been strongly linked to low HRV mediated by reduced parasympathetic activity . While iRecent work has revealed the potential of mind-body treatments  to critically reduce pain and opioid use after surgery. Surgery can precipitate both chronic pain and long-term opioid use ,59, withRecent studies of MBIs delivered during the perioperative period show promise for reducing pain and opioid use after surgery. Hadlandsmyth and colleagues  conducteAnother pilot study  similarlA larger, three-arm RCT (N=118) tested the effects of two mindfulness approaches for patients undergoing total joint arthroplasty: mindfulness of breath (MoB) and mindfulness of pain (MoP) . The twoFinally, a recent RCT by Flowers et al.  deviatedIn sum, brief psychological interventions delivered in the perioperative period show promise in preventing both chronic postsurgical pain and prolonged opioid use for many surgical patients. Psychological interventions for pain have historically been used to treat established chronic pain conditions and opioid use problems, or as one-time interventions to improve acute pain in a medical setting . Recent work has elucidated novel ways in which MBIs can be tailored to the perioperative period to prevent persistent pain and long-term opioid use after surgery in both opioid-naive patients and patients on pre-operative opioid regimens. Such MBIs show tremendous promise as supplemental treatments in the context of multi-modal management of peri- and post-operative pain. Many of these treatments demonstrate both short- and long-term benefits , with minimal potential for harms, or adverse effects; moreover, they can be applied as adjunctive treatments to existing regimens, as they do not interfere with (and may even offer synergies with) pharmacologic treatments, physical treatments such as physical therapy, etc. The brevity and low cost of mind-body interventions make them feasible to implement across settings and patient populations. It is noteworthy that many of these treatments require only a small number of sessions/visits, and most are amenable to remote delivery, making them potentially highly scalable.Historical impediments to psychological intervention, in general, include cost, logistical difficulties such as requirements for multiple in-person patient visits, and lack of access to providers with expertise in delivering these interventions. Increasingly, these barriers are becoming less salient as MBIs are available by remote delivery and covered by third-party payers. The delivery of psychological intervention during the perioperative period, however, introduces new challenges given certain logistical constraints such as timing of surgery. MBIs will need to be designed to maximize their flexibility in terms of format and delivery; already, a number of researchers have been creatively experimenting with: (1) the structure and timing of sessions  daily toll of opioid deaths is a clear call for ongoing work in this area. At this point, numerous hospital systems have begun implementing Enhanced Recovery After Surgery (ERAS) protocols to optimize hydration, nutrition, and pain control, leading to faster, safer, and more comfortable recovery from surgery. In general, most ERAS programs do not currently include MBIs in their multimodal treatment packages. Adding MBIs to existing ERAS protocols may present a valuable opportunity to further enhance the efficacy of a second generation of ERAS programs. Given the sizable (and growing) body of evidence that MBIs can improve acute outcomes in the peri- and post-operative space, and that MBIs show substantial long-term effects in preventing persistent pain and long-term need for opioids after surgery, such treatments appear to offer highly favorable risk-benefit profiles. Simultaneously, larger RCTs with flexible delivery formats and long-term assessment are needed to test and refine perioperative mind-body approaches to prevent the development of chronic pain and opioid use problems after surgery.


Disuse osteoporosis describes a state of bone loss due to local skeletal unloading or systemic immobilization. This review will discuss advances in the field that have shed light on clinical observations, mechanistic insights and options for the treatment of disuse osteoporosis. Clinical settings of disuse osteoporosis include spinal cord injury, other neurological and neuromuscular disorders, immobilization after fractures and bed rest . Furthermore, spaceflight-induced bone loss represents a well-known adaptive process to microgravity. Clinical studies have outlined that immobilization leads to immediate bone loss in both the trabecular and cortical compartments accompanied by relatively increased bone resorption and decreased bone formation. The fact that the low bone formation state has been linked to high levels of the osteocyte-secreted protein sclerostin is one of the many findings that has brought matrix-embedded, mechanosensitive osteocytes into focus in the search for mechanistic principles. Previous basic research has primarily involved rodent models based on tail suspension, spaceflight and other immobilization methods, which have underlined the importance of osteocytes in the pathogenesis of disuse osteoporosis. Furthermore, molecular-based in vitro and in vivo approaches have revealed that osteocytes sense mechanical loading through mechanosensors that translate extracellular mechanical signals to intracellular biochemical signals and regulate gene expression. Osteocytic mechanosensors include the osteocyte cytoskeleton and dendritic processes within the lacuno-canalicular system (LCS), ion channels , extracellular matrix, primary cilia, focal adhesions (integrin-based) and hemichannels and gap junctions (connexin-based). Overall, disuse represents one of the major factors contributing to immediate bone loss and osteoporosis, and alterations in osteocytic pathways appear crucial to the bone loss associated with unloading. Skeletal integrity is maintained by the process of bone remodeling, i.e., the balanced removal of old bone matrix by bone-resorbing osteoclasts and the deposition of new bone tissue by bone-forming osteoblasts . Since tClinically, disuse represents one of the major risk factors for osteoporosis, a widespread, multifactorial disorder characterized by low bone mass, impaired bone quality and increased risk of fragility fractures . It has The term “disuse osteoporosis” comprises various clinical situations of mechanical unloading or pathological immobilization associated with bone loss, including spinal cord injury , neuromuDisuse-associated bone loss has been outlined in many studies, which documented the magnitude of bone loss in a variety of disuse conditions early on. Dual-energy X-ray absorptiometry (DXA), regularly performed for the proximal femur and lumbar spine, represents the most established method to quantify the areal BMD and to determine the diagnosis of osteoporosis or low bone mass based on T- and Z-scores, respectively. DXA studies have been widely performed in disuse conditions, with both cross-sectional and longitudinal study designs.In patients with spinal cord injury, early studies have demonstrated that bone loss begins shortly after injury, with up to 2–4% bone loss per month in the sublesional skeletal sites during the first year . A peak To further address the magnitude and mechanisms of disuse-induced bone loss, a number of bed rest studies have been performed, with different approaches. Most studies also aimed to assess the recovery of bone mass in response to reambulation (reloading). In early studies, a similar amount of bone loss in the lumbar spine and hip of approximately 1% per month was detected in healthy males who had been followed up for 17 weeks . Other bIn addition to bed rest, the loss of BMD has also been well documented in spaceflight studies. Here, the rate of bone loss ranged from 1.07–1.92% per month in the proximal femur and 0.51–0.68% per month in the spine , or in o).Disuse osteoporosis includes not only systemic bone loss but also various conditions of local bone loss. In a previous study, magnetic resonance imaging (MRI) was performed in local disuse osteoporosis, where high signal intensity in the respective unloaded limbs was detected, indicating immediate changes following unloading . In a co2In previous clinical studies focusing on laboratory changes in bone turnover, disuse or unloading was associated with increased bone turnover (primarily bone resorption) across different disuse conditions such as spinal cord injury , 24, vegAlong with these previous findings on catabolic bone turnover dissociation following disuse, it is clear that the organism’s calcium metabolism is also impacted. Urinary calcium excretion was increased in patients during bed rest  and in iThe impact of mechanical load on the process of fracture healing represents a complex issue that must be considered separately from the aspects of disuse-induced alterations in bone remodeling outlined in this review. Nonetheless, it is known that the compromised mechanical environment associated with immobilization and load-bearing restrictions in the course of operative or conservative fracture treatment may be followed by a vicious cycle of disuse-induced fracture healing problems. While direct bone healing is usually achieved by high stability and low interfragmentary movement , indirect bone healing via callus formation is induced by a low degree of stability and considerable interfragmentary movement  . TherefoTo obtain more detailed data on the bone loss associated with disuse beyond DXA-based observations, volumetric and microstructural approaches, primarily peripheral quantitative computed tomography (pQCT) and, more recently, high-resolution peripheral quantitative computed tomography (HR-pQCT), have been introduced. The bone microstructural changes following immobilization have also been discussed in review articles , includiPrevious pQCT studies with cross-sectional study designs have demonstrated negative associations between the duration of disuse and bone microstructural parameters in patients with spinal cord injury, where steady states were reached after 3–8 years and the total amount of bone loss ranged from 25–35% (diaphyses) to 50–60% (epiphyses) , 57. DurDuring spaceflight, cortical and trabecular bone loss was observed in the tibia . NotablyThe recovery of bone mass in response to physical exercise programs, pharmacotherapy or both has been studied across different disuse and unloading models. Indeed, the most natural treatment for disuse osteoporosis is physical exercise or remobilization (loading) of the affected bones, although some of the disuse conditions per se do not allow remobilization. A recent systematic review found that the favorable effect of exercise on BMD in postmenopausal women is largely independent of the type of exercise . ExperimRegarding the optimal exercise program, various studies with different protocols have been conducted, from which diverging findings regarding their success could be derived. In individuals with spinal cord injury, an overall positive and site-specific effect of functional electrical stimulation-induced cycling exercise on bone mass has been observed –70. ThesThe fact that increased bone resorption plays a primary role in the development of disuse osteoporosis is supported by the findings of several previous therapeutic studies, in which antiresorptive treatment with bisphosphonates or the receptor activator of NF-κB ligand (RANKL) antibody denosumab attenuated bone loss , 75. ForTaken together, the treatment of disuse osteoporosis by combining bone-specific medications with physical exercise appears to be effective in at least partially counteracting the observed bone loss. In particular, the prompt increase in bone resorption markers after the onset of disuse  argues fTo decipher the mechanisms of disuse-induced bone loss, loading and unloading conditions have been modeled in a variety of human and animal studies. In one of our previous experimental human cadaveric studies analyzing the micromorphology of cortical bone, we found increased cortical porosity in long-term immobilization compared to controls and postmenopausal osteoporosis  Fig. 3aa3a, whicRegarding the evaluation of recovery or therapeutic effects in disuse osteoporosis, there have been many experimental studies taking advantage of animal models. One such study reported that different types of exercises  applied to rats with immobilization-induced bone loss were equally efficient in preventing bone loss , therebyThere have been a number of studies in rodents focusing on mechanical loading, bone remodeling and especially osteocyte mechanobiology. In mice, spaceflight led to both trabecular and cortical deterioration along with increased numbers of cortical empty osteocyte lacunae . Early sIn the search for molecular mechanisms involved in the pathogenesis of disuse osteoporosis, several other important signaling pathways and proteins involved in the process of mechanically driven bone remodeling have been discovered Fig. . Indeed,The mechanosensitive function of the skeleton was recently evidenced by the identification of mechanically activated ion channels of the Piezo family, specifically Piezo1 in osteoblasts and osteocytes , 8. InteAnother molecular example of musculoskeletal mechanotransduction, more specifically the close interaction between muscle and bone during this process, is the identification of the myokine irisin, a protein that is derived from muscle in response to exercise. Irisin injection increased cortical bone mass in mice, partly through suppression of sclerostin expression . In thisFinally, the molecular mechanosensors in osteocytes are the subject of ongoing research, as recently discussed in a detailed review article . BrieflyAlthough a number of fundamental questions concerning the clinical, molecular and therapeutic aspects of disuse osteoporosis remain unanswered, the combined effort of both clinical and basic research has revealed the microstructural and mechanistic basis of the profound negative effects of disuse on skeletal integrity. Clinical studies with real or modeled unloading conditions, including spinal cord injury, limb suspension, bed rest and microgravity (spaceflight), have demonstrated that early bone loss is characterized by a relative increase in bone resorption compared to decreased bone formation. As a consequence, combined cortical and trabecular microstructural deterioration was noted in most studies, with subtle disease-, sex-, site- and compartment-specific differences that can be accurately imaged using high-resolution CT-based techniques such as HR-pQCT. In a broader sense, disuse osteoporosis also includes clinical conditions of bone loss in response to local skeletal unloading, such as after surgery or around implants. Furthermore, full and timely recovery from bone loss may not be achieved by loading, but bone loss may be counteracted by high-frequency physical exercise programs and bone-specific agents such as bisphosphonates/denosumab and teriparatide. The use of animal models has allowed the cellular and molecular mechanisms of disuse-induced bone loss to be elucidated. Matrix-embedded osteocytes have been identified as the primary mechanoresponsive cell type translating mechanical into biochemical signals to orchestrate mechanically induced bone formation and remodeling, which is in fact a regulatory process with high complexity also involving neighboring bone cells. Osteocyte-specific proteins such as sclerostin and Piezo1 are involved in this process of mechanotransduction, and new therapeutic options have already been introduced; however, their efficacy needs to be clarified in further experiments and clinical trials acknowledging the mechanical environment.


Over the past few decades, natural-origin polysaccharides have received increasing attention across different fields of application, including biomedicine and biotechnology, because of their specific physicochemical and biological properties that have afforded the fabrication of a plethora of multifunctional devices for healthcare applications. More recently, marine raw materials from fisheries and aquaculture have emerged as a highly sustainable approach to convert marine biomass into added-value polysaccharides for human benefit. Nowadays, significant efforts have been made to combine such circular bio-based approach with cost-effective and environmentally-friendly technologies that enable the isolation of marine-origin polysaccharides up to the final construction of a biomedical device, thus developing an entirely sustainable pipeline. In this regard, the present review intends to provide an up-to-date outlook on the current green extraction methodologies of marine-origin polysaccharides and their molecular engineering toolbox for designing a multitude of biomaterial platforms for healthcare. Furthermore, we discuss how to foster circular bio-based approaches to pursue the further development of added-value biomedical devices, while preserving the marine ecosystem. The unparalleled biological diversity of the marine realm is an extraordinary source of a plethora of natural macromolecules with higher bioactivity and chemical novelty when compared with those extracted from terrestrial life forms , thus maAmong the source of natural compounds found in the oceans, polysaccharides obtained from marine organisms  are currWith the aim of maximizing the value of marine by-products towards the development of high value-added biomaterials, this review provides an up-to-date outlook on efficient, cost-effective and environmentally-friendly strategies that have been employed from the isolation of marine-origin polysaccharides up to obtaining the envisage biomedical device. Finally, we highlight some guidelines to facilitate the translation of marine-derived biomaterial platforms to the market and their benefits for society, while fulfilling the United Nations Sustainable Development Goals.Most conventional extraction processes  are characterized by long extraction times and comprise hazardous acidic and alkali treatments . These cAside from compressed fluids, extraction processes encompassing Subcritical Water Extraction (SWE), Ultrasound-Assisted Extraction (UAE) and Microwave Assisted Extraction (MAE) have also been used to surpass the bottlenecks of the standard extraction procedures, since they could be applied at pilot scale, thus offering the possibility to be integrated into a process chain within a biorefinery. This section provides an overview of the extraction methods applied to date to recover the most studied marine polysaccharides, including chitin, chitosan, hyaluronic acid, chondroitin sulfate, ulvan, alginate, fucoidan, laminarin, carrageenan and agarose .Chitin is the second most common polysaccharide in nature, after cellulose, being present in the exoskeleton of animals including crustaceans and shrimps. Chitosan (CHT) is a cationic polymer that is obtained by the deacetylation of chitin .Standard processes to extract chitin and CHT usually involve the use of high temperatures combined with strong harsh solvents, which consequently contribute to the generation of hazardous effluents and the quality decrease of the extracted polymers . In thisStreptomyces griseus. After 3 h treatment, the deproteination percentage was 91.1%  (HA and CS are part of the glycosaminoglycan (GAG) family and can be extracted from the cartilage, bones and fins of several marine organisms  . In geneetc.) .Both HA and CS display interesting physicochemical and biological properties and are widely present in the extracellular matrix (ECM) of connective tissues. Owing to their negative surface charge, they are capable to absorb a large amount of water, thus favouring tissue hydration. In general, HA is known for providing viscoelasticity, lubrification and immune system modulation, while CS displays anti-inflammatory activity, having a central role in the biological processes .Aetobatus narinari  through the use of papain (Raja clavata) was carried out by combining the enzymatic degradation approach with chemical hydrolysis through the use of papain in the presence of an alkaline hydroalcoholic solution  to breakdown the protein core and isolate HA and CS macromolecules from other polysaccharide complexes . Among tf papain . The enzsolution .Streptomyces griseus  is one of the sulfated polysaccharides extracted from the cell wall of green algae (Chlorophyceae). It can be isolated from seaweed from the genera Ulva and Enteromorpha, that usually have a negative connotation because they are associated with the phenomenon of eutrophication, a detrimental process for the aquatic environment . TherefoOwing to its variable chemical structure, different molecular weights have been reported for UL . Also, tUL polysaccharide has also shown to possess different biological properties, such antioxidant , antibacU. meridionalis and U. ohnoi , fucoidan (FU) and laminarin (LAM) are extracted from marine brown algae (Phaeophyceae). Additionally, FU can also be extracted from some marine invertebrates (sea urchins and sea cucumbers) . AlthougPolysaccharides extracted from brown algae display biological properties, including antioxidant, anticoagulant, antiviral, anti-inflammatory, immunomodulation, and antitumor activities, highlighting their importance in the biomedical field . These p−1) algae/water ratio) have afforded a FU extraction yield of 18.2%. In another work, the microwave–hydrothermal extraction was combined with supercritical carbon dioxide to remove the lipid fraction from the seaweed, prior to FU recovery  combined with hydrothermal treatment. One work has investigated a wide range of operational conditions , aiming at establishing the best ones that could maximize the FU extraction yield . The optrecovery . The hydApart from microwave, ultrasound-assisted extraction (UAE) has also been applied as an eco-friendly and time saving technique for the recovery of polysaccharides from brown seaweeds, namely laminarin and alginate . In bothMore recently, one work has reported the synergistic effect of coupling deep eutectic solvent (DES) with subcritical water extraction (SWE) of brown seaweed polysaccharides (FU and ALG) from Saccharina japonica . In thisCarrageenan (k-CG) and agar (or agar-agar) are marine polysaccharides derived from red seaweed (Rhodophyta) .via subcritical water extraction (SWE) using ILs as catalyst solvent  and deep eutectic solvents (DES) have aroused particular interest as green catalyst in the extraction procedure of carrageenan (k-CG). They can be used either alone or combined with another eco-friendly extraction technique to enhance the polysaccharide yield. For instance, extraction of k-CG from Kappaphycus alvarezii was carried out by using either deep eutectic solvents prepared by the complexation of choline chloride with urea, ethylene glycol and glycerol or by water as standalone extraction media . Interes solvent . Using a solvent . NeverthConcerning agar polysaccharide, one should be mentioned that its structure comprises agaropectin and agarose (AGR); the latter is a neutral and linear polysaccharide that results from enzymatic depolymerization and desulfation of agar  and its cooling leads to the formation of thermoreversible gels . Therefo2), carboxylic acid groups (–COOH) and aldehydes (–CHO)  .The modification of the polysaccharides’ structure through the introduction of acidic, basic, hydrophilic, hydrophobic, or other molecules with specific properties will not change fundamentally the polysaccharide backbone. However, it will unlock advanced modifications required for specific applications, and will change the final properties of the developed biomaterials. The development of novel chemical methodologies is an ongoing research area that is expected to become more important over the years, as the importance on using renewable starting materials and sustainable chemical processes are expanding. The methods described in this section  include Covalent chemical crosslinking is a widely used technique to enhance physical and chemical stability of the polysaccharide derivatives . In the via hydroxyl and amine groups is carried out through substitution reaction, achieving a higher substitution degree for the latter one due to its nucleophilic strength (higher for amines than hydroxyl groups)  into the polymer backbone to be further photo-crosslinked is a widely applied chemical route in natural polysaccharides and used in the fabrication of several biomedical devices, such as 3D hydrogel structures , cell en groups) . Concern groups) . In such groups) .via simple and high-yielding chemistry. This reaction still fulfills other requirements accounted in the broader Sharpless’ click definition (Click chemistry (CC) has emerged as a powerful tool for design and synthesis novel polysaccharide derivatives in a more controlled and modular manner , overcomfinition , namely The term “click-chemistry” is especially well-known when related to the copper catalyzed azide-alkyne cycloaddition (AAC). The AAC is still the leading technology among CC reactions due to the easy modification and incorporation of azide and alkyne groups into the polysaccharide structure. The application of AAC chemistry in polysaccharides has contributed to generate complex glycoconjugates that allowed the development of new biomaterials exhibiting improved properties and functions , assurinSeveral reviews have discussed the multiple applications of the (bio)conjugates arise from click-chemistry . Here, wOxidation in polysaccharides can occur at primary and/or secondary hydroxyl groups according to the chemical nature of the mild oxidant agent, thus producing different type of structures . Typically, the oxidation of primary hydroxyl groups in polysaccharides gives rise to an aldehyde or further to a carboxylic acid group with structural similarity to alginate, while oxidizing secondary alcohols leads to a ring-opening oxidative C–C bond cleavage giving dicarbonyl compounds .Selective oxidation has been attempted using nitrogen dioxide, nitroxyl radical 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or periodate salts as mild oxidants. Using nitrogen dioxide, primary hydroxyl groups at the C6 position can be oxidized into carboxyl groups. However, oxidative cleavage of polysaccharides may concurrently occur as side reaction, modifying the polysaccharide composition, which is a major drawback . In contvia Schiff base chemistry with compounds bearing amine moieties, thereby widely used for the fabrication of functional biomaterials as hydrogel crosslinking strategy and drug conjugation (Concerning secondary hydroxyl groups (C-2 and C-3), their oxidation is usually performed by using periodate that causes the oxidative scission of vicinal diols and, ultimately, the formation of dialdehydes or diketones. These groups exhibit high reactivity jugation .The development of polysaccharide-based fibers and particles has gathered considerable attention in the biomedical field due to their high surface-to-volume ratio, enhancing loading of cargo as well as efficient nutrient and metabolite transfer and cell-matrix interactions . AdvanceDespite the attractiveness of marine polysaccharides for producing biocompatible electrospun scaffolds, electrospinning of polysaccharide pristine solutions has proven to be challenging since they have poor solubility in common volatile organic solvents as well as low molecular weight, thus hampering stable fiber formation through conventional electrospinning methods. Likewise, marine polysaccharides are often combined with synthetic water-soluble biopolymers, including polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and polyethylene oxide (PEO), thus providing the desired electrospinnability for continuous fiber formation . In partin-situ) or after (post) electrospinning process, thus enabling the formation of stable hydrogel-based nanofibers. Moreover, crosslinking treatments also contribute to a sustained and prolonged drug release, thus preventing an initial burst release.Apart from water-based solvents, other green spinning solvents , namely Although glutaraldehyde has been reported as the most commonly used crosslinker agent , its hazvia triazole crosslinking between alkyne-modified LAM and hydrazine-modified LAM through standard microemulsion polymeric materials to prepare membranes, denoting fine-tuned properties and functions at the nanoscale, by resorting to green processing methodologies. Solvent casting/evaporation, LbL assembly technology, and polyelectrolyte complexation have been among the most commonly used methodologies to process biocompatible marine polysaccharide-derived self-standing membranes  of the dvia either solvent casting or thermo-compression molding resort to common organic acids for enabling its solubilization. As such, the scientific community has been looking for benign solvents to enable the production of biofilms. In particular, deep eutectic solvents have emerged as alternative green plasticizers for the sustainable production of more homogeneous, compact, and environmentally friendly marine polysaccharide derived composite biofilms/membranes, denoting improved mechanical properties and flexibility 100 free-standing membranes denoting a well-defined array of geometrical features at the microscale in which osteoblast-like cells tended to colonize preferentially , holdingHydrogels have been one of the bioengineering platforms highly explored in the biomedical field to mimic and restore the native tissues’ functionalities. They offer similarity to the ECM, high-water content, mechanical support for cellular activities, and the opportunity to incorporate different molecules . Owing to their structural similarity to ECM compounds, marine polysaccharides have also been extensively employed as precursor building blocks in the hydrogels’ design either in the form of injectable systems or as implantable 3D constructs .via Schiff base crosslinking chemistry  assembly technologies . In suchWith the significant advances on the hydrogels’ design, new classes of hydrogel-based biomaterials have been emerged such as cryogels  and ionoConcerning ionogels, they are polymeric networks that are swollen with ionic liquids (ILs). In particular, the use of ILs with polysaccharides are attractive to endow them with electrical properties towards the development of electroactive tissues . For instance, VPImBF4 ionic liquid was grafted onto methacrylated-chitosan upon UV-light exposure, enabling the formation of an electroactive hydrogel, which conductivity matched the one reported for spinal cord tissue . TherefoThe bioeconomy paradigm aims to foster a sustainable and circular economy supported by renewable biological resources. However, the growing interest on the use of marine organisms for a multitude of high-end uses may impact involuntarily their natural populations and negatively affect the marine ecosystems. Even marine taxa which have been explored for several decades are now being more closely monitored and their collection from the wild more strictly regulated. This is, for example, the case of Gelidium, the highly prized red seaweed used to produce Agar since the end of the 1800s. When mixed with water, this gelatinous substance forms hard gels and is used around the world by biologists to culture microorganisms. The growing concern with the conservation status of natural populations has led authorities from the main supplying countries  to restrict the harvest of Gelidium. With no signs for the global demand for Agar to slow down in upcoming years, with no unexplored wild populations of Gelidium available to supply algal biomass and with its production through aquaculture not being technically nor economically feasible, prices for this polysaccharide have skyrocketed.The scenario described above for Gelidium may eventually also occur for other seaweeds currently harvested from the wild and whose highly prized polysaccharides may also experience an increase in price. From brown seaweeds yielding FU , ALGs and LAM , to red seaweeds sourced for k-CG  and green seaweeds to produce UL , their natural populations may soon be unable to cope with the high demand if aquaculture is unable to boost supply. Seaweeds biodiversity is mirrored by their chemodiversity , as theiPenaeus vannamei). This is an excellent example of a circular bio-based approach that aims to add value to a side-stream (the exoskeletons) of a perfectly well-established value chain associated with the global processing of wild and farmed shrimp  or farmed in Asian countries , is certainly a sustainable way to obtain some polysaccharides of commercial relevance. For instance, while producing hyaluronan from the bacteria Streptococcus zooepidemicus remains as the most economically appealing approach (Isurus oxyrinchus) or the blue shark (Prionace glauca), whose populations worldwide are facing an unprecedented level of fishing pressure that is rapidly pushing them towards extinction  3 , by yielding health promoting biomolecules, as well as to SDG 12 (Responsible Consumption and Production), by fostering biorefinery approaches aligned with a circular bioeconomy, that allow to fully use marine resources from fisheries and aquaculture sourced for human consumption. Ultimately, by adding value to marine chemodiversity, the use of marine polysaccharides can raise awareness towards the need to preserve marine biodiversity and contribute to achieve SDG 14 (Life Bellow Water). Marine biomass produced under high-biosecurity standards, as well as that sourced from side-streams from the transformation industry of seaweeds and marine seafood will likely become the cornerstone of marine polysaccharides value-chains, in line with the Blue Bioeconomy framework currently advocated.The marine environment has proven to be an extraordinary source of bioactive molecules for a multitude of biomedical and biotechnological applications owing to their renewable character and very appealing physicochemical and biological properties. As such, marine-origin polysaccharides extracted from marine biomass are a highly valuable alternative to polymers obtained from petroleum sources, having a huge impact on the preservation of the environment, wellbeing of society, and the sustainability of our Planet. In fact, to date, marine biopolymers have already ignited a great interest in several commercial applications in different fields such as food, cosmetics, packaging, or biomedicine. However, when massively used, a major burden is imposed in their natural populations and marine ecosystems. Also, the chemical strategies most commonly employed to enable the extraction of marine polysaccharides encompass the use of hazardous chemicals and the generation of hazardous by-products, often being disposed, together with the marine biomass waste, into and contaminating the ocean, which imposes a major burden to the natural ecosystem and human health.In this regard, the continuous exploitation of efficient, cost-effective, environmentally-friendly and sustainable methodologies for enabling and valorising the efficient extraction of polysaccharide from marine biomass to produce added-value biomaterials for biomedicine is of upmost importance to address the United Nations Sustainable Development Goals (UN SDGs) and enabling a sustainable future globally.In this context, we would suggest some guidelines for the valorisation of marine biomass as high-added value products for healthcare applications: i) establish efficient, simple and eco-friendly extraction processes that could be applied in pilot plants; ii) unlock multiple functionalities for marine polysaccharides by combining computational and synthetic green chemistry towards the man-designed advanced biomaterials; iii) pursuit advanced research to exploit their full market potential encompassing scientists’ collaboration from interdisciplinary fields; and iv) promote synergistic interactions between academia and industries to foster marine-derived biomaterials into ready-to-use market products.


Osteoarthritis (OA) is the most common form of arthritis, affecting approximately 32.5 million adults in the United States. OA is characterized as a degenerative joint disease or “wear and tear” arthritis. Symptoms experienced by patients include, but are not limited to, swelling, stiffness, pain or aching, and decreased range of motion. The majority of individuals impacted by OA are over the age of 65. OA has long been thought of as an inevitable part of aging. Patients are typically diagnosed after the onset of symptoms once irreversible damage has occurred, such as the breakdown of bone and cartilage. Along with clinical presentations, medical professionals often relied on radiographic images to confirm the diagnosis of OA. Limited research has looked into how to catch OA early and stage patients in a pre-OA state, possibly preventing irreparable damage that is observable radiographically. This article presents the history, diagnosis, and classes of OA. In addition, we present multiple diagnostic tools currently used and others under investigation, including OA-specific biomarkers and electroarthrography (EAG). These tools show promise as aids in early OA diagnosis and intervention, ultimately slowing down or altogether stopping the progression of OA. In conjunction or individually, these techniques, if further developed, stand out as promising mechanisms that may decrease the current OA burden on the healthcare system. IntroductionEstimates in the United States show that approximately 80% of the population, 65 years or older have radiologic findings of osteoarthritis (OA), but only 60% experience symptoms . SuccessHistoryOA is a progressively degenerative disease of the articular cartilage which provides protection and a cushion for smooth gliding between joint surfaces . OA, rheOA diagnosis and trackingPatients suffering from OA tend to present with joint pain and reduced range of motion. The first attempts to radiographically classify OA were described by Kellgren and Lawrence in 1957 .OA is clinically diagnosed if a patient has usage-related joint pain in multiple joints, is over the age of 45 years, and has morning stiffness for less than 30 minutes. Because OA is a wear-and-tear disease, pain affects joints used with higher frequency and peaks during the middle of the day as usage increases. The first line imaging modality is plain radiographs and findings to diagnose OA include decreased joint spaces, formation of osteophytes, and subchondral sclerosis . Other iHere we present a review of a proposed diagnostic algorithm for OA that also lays out current guidelines, various minimally invasive treatments and surgical options, and two screening modalities that may be incorporated to diagnose patients in a pre-OA state.Mild versus moderate versus severe OAPatients with mild OA tend to have low levels of pain with preserved joint function and minimal impacts on their activities of daily living (ADLs). Those with moderate to severe OA tend to have persistent pain that significantly impacts their ADLs. Staging OA is critical to prepare a proper treatment protocol Figure . Here weThe American College of Rheumatology/Arthritis Foundation updated their guidelines in 2019 for the management of OA in the hand, hip, and knee . These gMinimally invasive OA managementIntra-articular corticosteroid (IACS) injections are commonly first-line for any patient presenting with OA-related pain, however, historically they have remained controversial . In someReports have found that IACS injections only provide short-term relief, and possibly can have negative effects on cartilage. These studies have suggested against IACS injection use as a long-term therapeutic treatment , 14. ConThe importance of conservative management as the first-line option, such as physical therapy (PT), is key due to findings that show over a one-year period, less pain and functional disability were seen in patients compared to IACS injections . Even asOther intra-articular injection options include hyaluronic acid (HA), platelet-rich plasma (PRP), and mesenchymal stem cells (MSCs). HA derivative injections mimic natural synovial fluid, providing lubrication and protection to articular surfaces. However, the benefit of their use has limited evidence and they remain controversial . PRP injThe American College of Rheumatology/Arthritis Foundation’s updated guidelines for managing OA in the hand, hip, and knee gave specifics regarding various joint injections . IACS inTopical solutions such as capsaicin have been around for many years as a non-systemic relief cream for peripheral pain. Capsaicin modulates the transmission of pain from peripheral nerves by depleting the stores of a neurotransmitter substance P at sensory nerve endings and was proven to be superior to placebo in providing relief for OA-related pain , 23. TopSurgical treatments for OA Final OA management requires referral to an orthopedic surgeon for surgical considerations in patients with moderate to severe OA who have not benefited from previous interventions. Surgical options are limited based on the specific joint. Surgery ranges in invasiveness from arthroscopic debridement to partial or total arthroplasty. During arthroscopic surgery, the joint is washed out to remove debris or crystalline products and debrided at the articular surfaces. The goal of arthroscopic surgery is to decrease pain caused by osteophytes and improve the overall range of motion . A signiTotal knee arthroplasties (TKAs) and total hip arthroplasties (THAs) are surgeries used as definitive treatments for patients who have failed to have relief from previous OA interventions. Although there have been recent advances in certain surgical approaches, arthroplasty surgeries commonly involve large incisions, foreign prosthetics, and intensive recoveries . Hips anCurbing the burden of OA through early diagnosisThere currently exists no clinical method to detect early OA. Two areas have been explored experimentally to possibly stage a patient as pre-OA: fluctuations in electrical signals generated by articular joints and systemic biomarkers. Below, we review current research on each of these modalities in an effort to highlight how they might be used in the diagnosis or staging of pre-OA. This is particularly important when considering the invasiveness and high cost associated with current staging and treatment practices.BiomarkersBiomarker levels are often screened for through routine blood draws and, if developed further, offer a cost-effective option for pre-screening, diagnosing, or staging OA. Biomarkers in circulation are under investigation as having a role in understanding the progression of OA and as tools to assess the outcomes of clinical interventions. Bauer et al. proposed the BIPED  biomarker classification system to provide a framework to characterize OA biomarkers . PromisiThe pathogenesis of OA involves the release of alarmins, such as 14-3-3-eta, that bind to pattern-recognition receptors (PRRs) on macrophages, which in turn leads to the release of proinflammatory mediators and an amplified inflammatory response . AlarminJoint electrical streaming potentialsThe first electrical signals observed from joints under loading conditions were called streaming potentials . The extUsing the idea that load-induced streaming potentials can be generated from an articular surface, authors in 2012 hypothesized that these potentials could be measured noninvasively with sensors surrounding the knee . The kneCartilage in 2020 [The latest publication on EAG started in 2013 as an abstract, eventually coming together as a published article in the journal  in 2020 . After c in 2020 . Forelim in 2020 . These l in 2020 . An inve in 2020 . This sa in 2020 . This st in 2020 . EAG coe in 2020 . EAG is a promising new technique to detect early arthritic changes and joint degeneration before radiological findings are found -42. HoweIn an attempt to provide relief, OA management currently focuses on early lifestyle modifications and noninvasive treatments. Management protocols can improve by targeting modifiable risk factors such as weight loss and low-impact exercises, being more individualized, and having minimal side effects. Providing more personalized management of OA could possibly halt or slow down the progression of OA. Measurable joint damage through conventional modalities is often permanent because articular cartilage has limited healing capacity due to low metabolic activity and limited blood supply. Systemic molecular markers and superficial measured electrical joint signals, that assess early articular changes or the predisposition of an individual to future damage, may lead to an earlier diagnosis in a pre-OA state and the initiation of early management. Early staging techniques will require advancements that are cost effective for the patient with minimal adverse effects. Further research should investigate how these non-invasive modalities can be used to target OA patients before joint and articular degeneration leads to permanent damage.


However, B cells are increasingly considered to have additional functions, supported by studies finding them to occur in highest numbers in chronic discoid lupus erythematosus (CDLE), a subtype in which autoantibodies are often absent. More precise knowledge of how CLE subtypes differ pathophysiologically may allow a tailored pharmacotherapy in the future, taking into account the specific molecular signature in relation to the morphologic subtype.Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune disease that may be limited to the skin or can be associated with systemic lupus erythematosus (SLE). CLE occurs in several morphologic subtypes ranging from isolated, disc-shaped plaques to disseminated skin lesions. The typical histopathologic pattern of skin lesions is named interface dermatitis and characterized by a lymphocytic infiltrate and necroptotic keratinocytes at the dermo-epidermal junction. Other histopathologic patterns primarily involve the dermis or subcutis, depending on the subtype. One critical mechanism in CLE is the chronic reactivation of innate and adaptive immune pathways. An important step in this process is the recognition of endogenous nucleic acids released from dying cells by various pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and other cytosolic receptors. Crucial cells in CLE pathogenesis comprise plasmacytoid dendritic cells (pDCs) as major producers of type I IFN, T cells exerting cytotoxic effects, and B cells, previously believed to contribute  Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune skin disease that can occur isolated to the skin or with additional systemic manifestation in several organs [systemic lupus erythematosus (SLE)] . CLE canThe classification of CLE subtypes, however, should not be understood too rigidly as overlaps in clinical and histological appearance are not uncommon. This also supports the assumption of Ackerman, who considers the different CLE subtypes as manifestations of the same pathological process . NeverthIn this review, we provide an overview of histopathologic patterns observed in different CLE subtypes. We also discuss the current concept of the pathophysiology of CLE. Here, we highlight the cell types and cytokines involved as well as the central mechanisms of chronic reactivation of innate and adaptive immune responses.In principle, active CLE is characterized by a hyper-activated type I interferon (IFN) pathway, which triggers an inflammatory response against lesional skin . This reThis vicious cycle can be triggered by provoking factors such as UV light, cigarette smoke and various drugs –16. Thesvia pattern recognition receptors (PRRs)  such as high mobility group box 1 protein (HMGB1), reflecting potential autoantigens –29. Accus (PRRs) . In plass (PRRs) . In keras (PRRs) –38. Seves (PRRs) , 40. Mors (PRRs) , 41, 42.APCs are known to induce the development and clonal expansion of autoantigen-specific B- and T-lymphocytes. Upon repeated autoantigen contact, activated B cells can differentiate into plasma cells to produce specific autoantibodies against nuclear components, and T cells can migrate into lesional tissue to assist in B cell activation and exert cytotoxic effects against keratinocytes, which in turn again leads to the release of endogenous nucleic acids, fueling the self-reinforcing vicious cycle of lesional inflammation .via lipofection—a process known to be mediated by the antimicrobial peptide cathelicidin ..via lipoThe inflammatory cell infiltrate in LE skin lesions varies in composition and distribution depending on the subtype , 11, 50.The original concept of CLE pathogenesis primarily ascribed a dominant role to the adaptive immune system. This concept emerged primarily from observations in SLE that began about 70 years ago, in which autoantibodies directed against host structures (such as nuclear components) are considered particularly important , 53. HowCLE is considered a Th1-dominated disease. The pathogenic importance of T cells results from their cytotoxic function, which they exert against structures of the skin, particularly basal keratinocytes , 8, 55. According to the classical concept, B cells are crucial in LE pathogenesis because of their ability to produce autoantibodies against nuclear components. However, this concept could not explain the occurrence of the disease in autoantibody-negative patients . InteresThese findings suggest that B cells have other functions besides autoantibody production such as antigen presentation, co-stimulation and cytokine secretion, remaining to be explored in further studies. For instance, an ongoing study investigates the therapeutic effect of the BAFF inhibitor and human monoclonal antibody Belimumab on lesional B lymphocytes in CLE and aims to further characterize these cells (EudraCT 2017-003051-35).via endocytosis with the help of CD32 receptor  cluster in the dermis to locally produce massive amounts of type I IFN and thus drive the lesional inflammatory process , 62. Thereceptor . They arreceptor , 68. Morreceptor .In LE skin lesions, neutrophils accumulate primarily during the initial phase of CLE lesion development . NeutropAnalysis of gene expression from skin lesions of CLE patients has greatly improved our understanding of immunopathological mechanisms and revealed interesting molecular structures for targeted therapies. A hallmark of all CLE subtypes represents a strongly upregulated IFN pathway as discussed below. Other important signaling pathways include TLR-dependent and TLR-independent  pathways and their downstream signaling pathways , which are known to facilitate the chronic reactivation of innate immune pathways by nucleic acids and other DAMPs. Another well-described pathway in CLE is the JAK-STAT pathway, which is critical in pathogenesis as it is responsible for transmitting IFN signals , 72, 73.The major pathway in CLE pathogenesis is the type I IFN pathway, which has been shown to be upregulated independently of the specific subtype and lead to the suggestion of CLE as an acquired interferonopathy , 74. TypType III IFNs have also been detected to be increased in CLE patients with active skin lesions . The mai−/− knockout and when treated with TLR7 agonists, underscoring the role of innate DAMP signaling in CLE  the molecular mechanisms in CLE pathophysiology and (ii) the effects of blocking or modulating a pathway that is part of a complex network is essential. In addition, it is important to determine to what extent the morphological CLE subtypes differ at the molecular level and what leads to the manifestation of a particular subtype. If there are typical molecular features for each subtype, identification of biomarkers would be desirable to reveal the leading mechanisms even in challenging cases with overlapping clinical manifestations. Another task is to better understand the mode of action of therapeutic agents. For instance, it remains to be determined whether and how B-cell-focused strategies such as BAFF inhibitors differ in efficacy in patients frequently featuring autoantibodies (such as ACLE and SCLE) and in patients with particularly high B cell levels in skin lesions lacking autoantibodies (such as CDLE), as they both feature B cell associated processes. A deeper understanding of these mechanisms will hopefully allow stratified or even personalized therapy options for patients in the future.CLE can be a highly burdensome disease for patients. Fortunately, more insights into CLE pathogenesis have been gained in recent years. A key mechanism is the chronic reactivation of innate immune pathways. TF and JW performed the literature review and wrote the manuscript. TF, LdV, and JW designed the figures. CB and LdV added intellectual content and critically revised the manuscript. All authors approved the final manuscript for publication.The authors have been an advisor and/or received speakers' honoraria or travel expense reimbursements and/or received grants and/or participated in clinical trials of the following companies: CB: Novartis, L'Oreal, GSK, and UCB. JW: GSK, Incyte, Novartis, Medac, Merck/Serono, Roche, Actelion, Pfizer, Spirig, ArrayBio, and Biogen.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.