The high prevalence of fractures and the essential role that imaging examinationsplay in this scenario require the radiologist to be familiar with their mainpatterns, especially those of fractures for which the management is essentiallysurgical. This pictorial essay presents a series of illustrative cases and abrief review of the literature, the aim being to demonstrate some of the mainfractures of the appendicular skeleton that require surgical management,grouped, didactically, by the joint affected. Radiographic and computedtomography studies of illustrative cases were selected from the imaging archivesof our facility. Theimaging examinations usually performed in this context are conventional radiographyand computed tomography (CT). The former is used as an initial imaging method,because it demonstrates bone structures well, is widely available, and isaffordable, whereas the latter allows three-dimensional reconstructions,visualization of structures in other planes (providing a more satisfactoryassessment of complex fractures), and better evaluation of soft tissues, such asblood vessels. The evaluation of these imaging examinations is sometimes achallenging task, especially in patients with fractures for which the management isessentially surgical, in which a delayed diagnosis can have catastrophicconsequences, as is the case for the various types of fractures addressed in thisstudy. Therefore, it is essential to recognize the main patterns of fractures andtheir mechanisms of trauma, as well as imaging findings that in themselves denote agreater need for surgical treatmentThis pictorial essay presents illustrative cases of the main fractures of theappendicular skeleton that require surgical management, grouped, didactically, bythe joint affected. The focus is on X-ray and CT, the two methods most commonly usedin emergency settings.,2, asillustrated in Fracture of the proximal humerus is one of the most common fractures of theappendicular skeleton, accounting for 4.0-5.7% of all cases, and can occur inlow- or high-energy trauma, such as falls in the elderly and motor vehicleaccidents in young people. The Neer classification is used in order to assessand determine guidelines for the treatment of these fractures, classified as oneto four parts: humeral head; greater tuberosity; lesser tuberosity; anddiaphysis. Deviation between the parts is defined as when the distance betweentwo parts is > 1.0 cm or the angle is > 45°,3. Therefore, inpatients with posterior dislocation of the elbow and fracture of the radialhead, a CT study is recommended as a means of obtaining a more accuratediagnostic accuracy , hemorrhage being the main cause of death. The radiologicalevaluation begins with the acquisition of X-rays in anteroposterior, oblique,inlet and outlet views .Complem,8.Intertrochanteric fractures are extracapsular fractures involving the greater orlesser trochanter .Because ,8.Femoral neck fracture is most common in the elderly and in females. Suchfractures are associated with a high mortality rate, the one-year mortality ratebeing approximately 25%. The mechanism of trauma in femoral neck fracturedepends on the age and functional status of the patient, being a low-energylateral fall with impact on the greater trochanter in older patients andhigh-energy trauma in younger patients. The most widely used classification isthe Garden classification, which describes four categories of femoral neckfracture: incomplete or valgus impacted (type I); complete and nondisplaced(type II); complete and partially displaced (type III); and complete and fullydisplaced (type IV), as shown in ,9 :shear, depression, or both of the medial plateau (Type IV); bicondylar plateaufracture (Type V), as depicted in Tibial plateau fractures are joint fractures of the proximal tibia that aretypically accompanied by injuries to soft tissues such as ligaments and menisci.The most common mechanism is trauma with an axial force vector, such as thatcaused by a fall from a great height. The classification system that has longbeen used is the Schatzker classification, which divides tibial plateaufractures into six types, depending on the condyle affected and the presence orabsence of joint depression, shear, or both. The first three types are puretibial plateau fractures, typically associated with low-energy trauma: shearfracture of the lateral plateau fracture without depression (type I); shear anddepression of the lateral plateau (Type II); and isolated depression of thelateral plateau (Type III).The remaining three types are more severe andassociated with significant soft tissue damage.Ankle fractures are common, occurring mainly in inversion or eversion injuries.The indications for surgical treatment include loss of joint congruence,displaced fracture of the medial malleolus, fracture of the lateral malleoluswith shortening or displacement, bimalleolar fracture, and open fractures.Attention should be paid to injury of the tibiofibular syndesmosis , which i,10.Lisfranc ligament injury is characterized by traumatic disjunction of the medialcuneiform joint and the base of the second metatarsal. Lisfrancfracture-dislocation is a partial or complete loss of bony and ligamentousstability at the level of the tarsometatarsal joint . LisfranThe findings, classifications, and indications for the surgical management of thefractures of the lower limbs described in this essay are summarized in Fractures are common findings in emergency radiology practice. Therefore, it isimportant for radiologists to be familiar with the main mechanisms of trauma and theimaging findings that inform orthopedist decisions regarding the appropriatesurgical approach.


In an age of globalisation and hyperconnectivity, the COVID-19 pandemic has caused unprecedented and sustained impact worldwide. This article discusses issues related to (science) communication at different phases of the COVID-19 epidemic timeline. We consider the role of communication for prevention from the ecological perspective, taking into consideration that many emerging pathogens, including COVID-19, likely arise in part due to anthropogenic changes to natural environments. Communication forms part of the early response setting the scene for public buy-in of public health interventions at the start of an outbreak, as well as to maintain precautions over time. Finally, communication is a key element in increasing acceptance for new tools that require mass uptake to be effective, as seen with roll-out challenges for the COVID-19 vaccines, which faced heightened concerns of efficacy and safety while mired with rampant misinformation. Ultimately, strategies for prevention of viral epidemics such as COVID-19 must include communication strategies at the forefront to reduce the risk of the emergence of new diseases and enhance efforts to control their spread and burden. Despite key themes emerging, what constitutes effective communication strategies for different people and contexts needs to be investigated further. The coronavirus disease 2019 (COVID-19) pandemic, caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly emerged and significantly altered modern life across the globe . DespiteAn underlying element of this threat is our limited awareness and appreciation of the anthropogenic factors behind the emergence and persistence of pandemics, which reduces our ability to prevent and manage these risks to public health . ConsequWhile the sustainable development goals (SDGs) were established in 2015 to provide unified interlinked direction for research and development globally, the ideas of “One World, One Health”™, seeking to harmonise disciplines across the life and environmental sciences with a special focus on zoonotic diseases, have been articulated since 2004 if not earlier . In 2013Wildlife is more susceptible to contracting or transmitting zoonosis in recently deforested landscapes , as the High levels of stakeholder awareness and engagement on risks posed by unsustainable development are thus required to ensure effective preventive interventions against future disease outbreaks. While environmental education serves as a valuable form of science communication providing scientific knowledge, building foundations on the importance of biodiversity conservation and highlighting public roles for conservation action , key sciIn deforested landscapes, wildlife is not only threatened by habitat destruction, poaching and wildlife trade, but also through exposure to human communities where there is overlap between fragmented forests and areas with increasing anthropogenic presence. For COVID-19 in particular, the hypothesised viral spread from bats through pangolins is due to weakening of the intermediate host’s immune system during the wildlife trading process and in captivity, further exacerbated by crowded conditions in wildlife wet markets thereby accelerating interspecies transmission . Thus, oOne opportunity  for public engagement centers on modulating perceptions of “normal” public-wildlife contact. In many Southeast Asian countries, macaques living in forest fringes often become reliant on food handouts from the public or tourists who directly feed them believing they are helping care for the animals, and/or through foraging of discarded food scraps that are not appropriately managed . HoweverInadvertently, the profound impacts of COVID-19 outbreak have refocused global attention towards the importance of understanding the origins of the coronavirus and zoonotic transmission risks, and the popularity of consuming bushmeat and exotic medicines in China has declined since the pandemic compared to earlier years ,38. PivoThe COVID-19 pandemic has shown that acknowledging and communicating the problem is the first step to adopting solutions. Barriers to these efforts relate to the challenges in convincing decision-makers pertaining to risks and appropriate mitigation when evidence is absent or limited as was seen early in the pandemic. Further complicating matters is the tangled web of competing and often contradictory communication delivered to the public by various agents. Where the epidemiology of COVID-19 was concerned, governments and public health authorities struggled in the early days of the pandemic to arrive at a consistent narrative that could elucidate risks and mitigating factors surrounding the disease . This waOne of the biggest early controversies that detract from effective action pertains to the airborne nature and effectiveness of mask-wearing for controlling COVID-19 . While pAs a result, even after it was evident that aerosolised SARS-CoV-2 persisted in areas with low ventilation , and thaEventually, as acceptance for mask-wearing along with other precautions such as social distancing increased due to demonstrated and perceived effectiveness , there wIn particular, lockdown and social distancing rules should not be a wish-list of ideals from governments without considering the experiences of the people and the need to balance practicability with potential and perceived public health gain . RegulatIn fact, previous work informed by the health belief model  and protA more effective strategy may be to communicate the concept of individual COVID-19 risk and harm reduction based on dynamic social situations rather than ideals , while wThe COVID-19 pandemic not only caused unprecedented level of global disruption, it also spurred an unprecedented level of global and scientific cooperation to develop new tools, ranging from protective and monitoring devices, drugs, software applications, and vaccines. Despite the fact that most vaccines require over five years to develop from etiological discovery, the first COVID-19 vaccine took under 6 months to reach Phase III clinical trials and over three vaccines were approved for emergency use less than a year after the pandemic began ,88. WhatUnlike communication about transmission dynamics of an unpredictable novel virus, communication regarding new tools can be better strategised even before the tools are ready for roll-out since their development is arguably within human or decision-maker control . While tThe unfolding discourse of risk of vaccine side effects versus risk of COVID-19 underscores the need to re-evaluate the basic understanding and the emotional response to scientific concepts for the majority of the population , and addThe emergence of COVID-19, a new and highly contagious disease, stimulated high anxiety and fear. Yet, it was also soon established that infection was only potentially severe in certain groups in the population, with a larger majority manifesting mild or no symptoms. This combination of indiscriminate risk of infection but imbalance in risk of disease quickly brewed some negative social sentiments ranging from apathy, polarisation, frustration, judgment, and worse, discrimination against people seen to pose risk of infection. COVID-19 patients in general faced varying levels of social stigma, exacerbated further by any existing race-, religion- or social class-based discrimination . FurtherBeyond stigma, the pandemic has taken an immeasurable toll on mental health and wellbeing of individuals across the globe. The highly charged atmosphere surrounding COVID-19—characterised by widespread signals of alarm on public media and in social circles, disruptions to daily life activities , economic uncertainty, and bottlenecks in healthcare—extends the burden of the disease beyond those who contracted it. Manifestations of mental health decline include anxiety, insomnia, perception of insecurity, anger, increased use of health devices for fear of illness, and behaviors risky for health . Healthcare workers also reported the psychological burden of making difficult triage decisions when resources were stretched and also fearing for their own safety. The psychological impact of COVID-19 on the general population parallels those previously seen during SARS, natural disasters, and even armed conflicts , hence tLockdowns and strict restrictions were always known to be temporary solutions to controlling COVID-19 ,66. HoweAs case numbers continue to decline due to successful implementation of public health interventions and tools, risk perception may decline correspondingly. This then challenges any need to quickly respond to re-emergent threats such as local outbreaks that require drastic implementation of measures to be rapidly contained. Indeed, sustaining pandemic control poses unique challenges due to labor and expense required to maintain surveillance and vaccination coverage against a perceived diminishing threat, as seen in the case with measles . The perNevertheless, Australia, like many countries, continue to face significant challenges in delivering COVID-19 vaccines. This has been due to a combination of supply and administration issues , but earAs the vaccines have only been shown protective against disease and not infection, elimination strategies through herd immunity will likely require extremely high proportions of vaccinated populations , withoutCOVID-19 emerged as a potential pandemic late December 2019. With the exception of close neighbors to China such as Taiwan and Hong Kong, as well as New Zealand, strict border control measures were only put in place several months later elsewhere across the globe ,66—likelBeyond border closures, other aspects of Taiwan’s early response were exemplary in preventing community transmission or the need for a lockdown thus far. On top of ramping up supplies, diagnostic testing, and enforcing mandatory mask-wearing, Taiwan’s COVID-19 dedicated Central Epidemic Command Center (CECC) established since late January 2020 also made fighting misinformation a key part of the CECC’s mandate, holding tight control as the only source for COVID-19 related information in Taiwan to prevent the spread of fake news . StandouTraditionally, health communication frameworks are mainly premised on the health belief model which targets behavior change at the individual level e.g., patient or caregiver ,146,147.Another key theme in combating COVID-19 is the importance of trust, empathy and compassion in crisis communication at various levels ,153. WitWith the mysterious COVID-19 unfurling in the era of social media, the nuanced impact of communications on social networks and multilateral information sharing on the success and challenges in various efforts for COVID-19 control cannot be trivialised. Whether the influence of social media communications was a boon or a bane for epidemic control remains debatable ,157. TheFinally, to truly prevent the emergence and spread of viral diseases such as COVID-19, the delicate web of human action and its impact on environmental, biosphere integrity, and the health of the people and the planet must continue to be communicated and imprinted into our social psyche. This includes targeted awareness campaigns on aspects of conservation and sustainability, infectious disease and One Health for different age and stakeholder groups. Further, the elephant in the room, the barriers in communication between disciplines, stakeholders and stewards, must be actively addressed. As long as problems are only approached unilaterally, we may be doomed to constantly miss the forest for the trees, and find ourselves painfully underprepared even for the next pandemic. While some aspects of silos may be necessary due to the practicality of compartmentalization in pursuit of science, its restrictive effects arise from lack of opportunity to interact and transfer knowledge . A positClearly, in the case of COVID-19, the stellar growth in scientific knowledge and progress in development of tools to mitigate the spread and impact of the disease is only half of the battle won. An equally important challenge to overcome is ensuring that communication of the knowledge and tools acquired are vulgarised in a way that enables public health strategies to succeed with not only regulation and enforcement, but through community engagement and support. While it bears to say we must communicate more effectively, the methods for communication about viral diseases and their means of control are also scientific challenges, which require better consolidated research to determine effective strategies for bridging different disciplines and groups of people under different contexts. Ultimately, the aim of effective communication is not to overwhelm people with information that they have difficulty making sense of, but instead to elevate their self-efficacy to act on the information they have. Moving forward, building trust and harnessing transdisciplinary voices that deliver clear, empathetic, and actionable messages using effective communication tailored for different purposes and audiences is critical for prevention and control of future viral diseases, particularly those that are as explosive as COVID-19.


Crop yield and quality are important traits with many components. Crop yield is significantly correlated with flowering time or heading, plant height, branching or tillering, grain number, and grain weight, whereas quality is a result of metabolic flux attributed to compound biosynthesis and metabolism . AlthougSeveral studies have been conducted on the genetic control and identification of important genes in crop yield and quality traits , with a In this Research Topic, we collected investigations on regulatory mechanisms underlying interactions between the environment and genetic factors and their effects on crop yield and quality. The Topic includes four research papers and one review.Razzaq et al. reviewed candidate genes controlling fiber quality in sub-genomes A and D of cotton (Gossypium hirsutum), finding that chromosome 7 carries abundant SNPs for stable and potent QTLs for fiber quality.Because of the complexities of the environment, which include climate, soil condition, and crop management practices, one of the most difficult aspects of predicting crop yield is applying appropriate models including climatic and phenotypic data and molecular markers . ClimatiJarquin et al. applied five models with climatic information to study the genomic prediction efficiency of corn yield. The exclusion of the environment led to greater error variation, implicating the importance of environmental effects. Improvement in the prediction ability has been observed when the environmental data is included, as compared to prediction ability with only parental data . The prediction ability also depends on the nature of the data provided. Normally, prediction models that used tested genotypes in the observed environment were the most accurate, whereas models based on both untested genotypes and unobserved environments were the least accurate. In partial summary, including environmental factors improves the genomic prediction of crop yield.+. There is a type of NXH (sodium/hydrogen antiporter) gene family that can regulate the equilibrium of sodium and hydrogen ions. Fu et al. found that NXH genes are a large family in the four cotton sub-species. Interestingly, these genes can be divided into three types: endosome-, plasma membrane-, and vacuole-type. The respective types may be responsible for the different functions, such as the control of gene behavior, transport of sodium and hydrogen exchange, or accumulation.Regardless of the efficacy of genomic prediction, breeders and researchers should further elucidate the effects of different types of environments on crop yield and quality. One of the problems in obtaining high yields is soil stress, such as salinity. Crops have very strong plasticity and multiple pathways to avoid salt stress . When pl2+ ions, as a means of signal transduction, play a significant role in mediating salt stress , GmNAC81, via overexpression under drought stress. Because GmNAC81 acts as an executioner of the cell death program, the plants had increased sensitivity to drought stress, exhibiting faster water loss in the leaves and reduced photosynthetic efficiency. Furthermore, the expression of key regulators and effectors of ABA signaling was blocked when GmNAC81 was over-expressed. Knockout of the gene via genome editing may provide more evidence to elucidate its function.Drought stress is another adverse and widespread environmental response that severely affects crop yield . AlthougIn conclusion, precise genomic prediction using environmental, phenotypic, and genomic data is a desirable trend for breeding. The mechanism of even a single environmental stressor, such as salt or drought stress, can be modulated by different gene families, for example including NXH, CAMTA, and NAC. Further identification and evidence of the functions of these transcriptional factors are of importance.


Therefore, the improvement of cognitive performances has become a primary goal in the care of patients with SCZ, especially in the first phases of the disease, as early interventions may favour better long-term outcomes. Cognitive remediation (CR) is a behavioural training aimed at improving cognitive functions with the goal of durability and generalisation in everyday life. Neuroimaging studies suggest that CR leads to neuroplasticity in chronic SCZ, whereas only a few studies tested the neural effects of CR in the early phase of the disease. Thus, in this review, we aimed at summarising CR-induced structural and functional brain changes in early SCZ. Existing evidence showed a protective effect of CR on grey matter volume in selected medial-temporal  and thalamic regions whereas functional changes affected mostly dorsolateral prefrontal and insular cortices both associated with improvements in cognitive performance and emotion regulation. Overall, CR in early SCZ appears to be associated with neural adaptations mostly allocated in prefrontal and limbic regions, however future longitudinal studies are needed to clarify whether the positive effects of cognitive training persist over time. It may also be interesting to investigate whether the application of CR in the early  The inclusion criteria are: (i) original publication published in a peer-reviewed journal, (ii) English language, (iii) the use of a structured protocol for CR training, (iv) the inclusion of a comparison group undergoing a control therapy and (v) application of structural or functional neuroimaging techniques. After title and abstract screening, four studies were identified and included in the review, three of which used the same cohort of patients  in CET compared to EST over the two years of treatment, which was associated with neurocognitive improvement. Conversely, patients treated with EST showed no changes in functional connectivity over time  . Particularly, the long-term effect of CR interventions on brain plasticity has not been investigated yet. As such, future studies  are needed to assess whether CR may be considered a sustainable approach with long-lasting positive effects on cognitive and neural alterations of patients with SCZ. Particularly, we warrant the conduct of longitudinal studies starting from the very early stage of the illness to clarify whether the application of CR in the early


Introduction: Systemic sclerosis (SSc) is a systemic immune-mediated disease, featuring fibrosis of the skin and organs, and has the greatest mortality among rheumatic diseases. The nervous system involvement has recently been demonstrated, although actual lung involvement is considered the leading cause of death in SSc and, therefore, should be diagnosed early. Pulmonary function tests are not sensitive enough to be used for screening purposes, thus they should be flanked by other clinical examinations; however, this would lead to a risk of overtesting, with considerable costs for the health system and an unnecessary burden for the patients. To this extent, Machine Learning (ML) algorithms could represent a useful add-on to the current clinical practice for diagnostic purposes and could help retrieve the most useful exams to be carried out for diagnostic purposes. Method: Here, we retrospectively collected high resolution computed tomography, pulmonary function tests, esophageal pH impedance tests, esophageal manometry and reflux disease questionnaires of 38 patients with SSc, applying, with R, different supervised ML algorithms, including lasso, ridge, elastic net, classification and regression trees (CART) and random forest to estimate the most important predictors for pulmonary involvement from such data. Results: In terms of performance, the random forest algorithm outperformed the other classifiers, with an estimated root-mean-square error (RMSE) of 0.810. However, this algorithm was seen to be computationally intensive, leaving room for the usefulness of other classifiers when a shorter response time is needed. Conclusions: Despite the notably small sample size, that could have prevented obtaining fully reliable data, the powerful tools available for ML can be useful for predicting early lung involvement in SSc patients. The use of predictors coming from spirometry and pH impedentiometry together might perform optimally for predicting early lung involvement in SSc. Systemic sclerosis (SSc) is a systemic immune-mediated disease, characterized by fibrosis of skin and organs, featuring one of the greatest mortality ratios among rheumatic diseases . Recent Notably, from the clinical point of view, one of the most important challenges in the management of this pathology is represented by the risk stratifications of complications and, ultimately, death; as a matter of fact, although no disease-modifying drugs have been found in SSc, early screening and management of patients improves survival . HoweverTo this extent, technological advances can help the clinicians screening the most functional diagnostic methods to be picked up, supporting diagnosis and, in some instances, clinical decision.In this framework, Artificial intelligence (AI) will probably play the starring role in the future of medicine. Indeed, increasing growth in the interest towards AI is seen in (bio)-medical research, driving valuable outputs in the framework of the “p4 medicine” . NotablySpecifically, within the field of immune-mediated diseases and, more in depth, considering the SSc as the reference model, the application of AI for supporting the diagnosis of SSc can confirm that the possibility exists for the early prediction of ILD, anticipating functional signs shown by the spirometry and pH-impedentiometry. This would eventually enlarge the indication of HRCT foreseen in the International guidelines ,15.Considering the existing literature in the field, ML was employed in identifying SSc in electronic records. Notably, Jamian and colleagues , using rThe association between biomarkers and phenotype of the disease using AI was investigated in some works published to date, displaying overall good outcomes, but leaving room for further investigation, especially in terms of the amount of the biomarkers taken into account. More specifically, Huang and colleagues  applied In light of the growing demand from the clinical world, and considering the current diagnostic gaps experienced in the specific applications of the SSc, in the present research we used ML to predict early lung involvement in SSc from both clinical and instrumental data—for the first time using together both these categories—evaluating this promising approach for early diagnosis in the framework of personalized medicine.We retrospectively evaluated 38 patients at the Department of Internal Medicine, University of Genoa, and at the Radiology Unit, IRCCS Policlinico San Martino, Genoa. All patients signed written informed consent in compliance with the regulations of the host institution and were treated in accordance with the Declaration of Helsinki.We collected clinical data from esophageal evaluation  and pulmonary evaluation (pulmonary function tests) once for each patient. Of note, the reflux disease questionnaire (RDQ) allowed the evaluation of reflux esophagitis, collecting information about the frequency and severity of upper gastrointestinal symptoms .Radiological data concerning esophageal diameter and severity of lung involvement were also collected on HRCT images. The widest esophageal diameter (dmax) and the widest esophageal area (area max) were calculated by placing a freehand region of interest (ROI) upon the esophageal contours on para-axial images perpendicular to esophageal lumen where the widest esophageal sectional area was visually assessed. Esophageal diameter and area measurements were also conducted at 30 mm (D3), 50 mm (D5) and 70 mm (D7) from lower esophageal sphincter (LES), corresponding to the points on which the impedance pH test is conducted. LES position was conventionally set at the level of the diaphragmatic plane.Lung severity assessment was evaluated by a radiology resident blinded to the pulmonary function tests. The Warrick score (WS), a semiquantitative score based on pulmonary anomalies on HRCT , was usePulmonary involvement was defined upon the presence of signs of interstitial lung disease on HRCT with 6 out of 24 patients having interstitial lung disease on HRCT.The overall dataset employed, with means and standard deviations (SDs), ranges and distribution type of the 23 variables, including the outcome, is shown in As briefly mentioned above, the Machine Learning part was aimed at identifying how the clinical variables were predictive of the clinical outcome, calculated as the WS defined in the previous paragraph, and suggestive of the severity of the clinical condition.To setup the ML approach, we programmed the R language and used the open source RStudio , version 1.3.1093 for Windows, available with the GNU Affero General Public License.The dataset employed for ML was complete, without occurrence of not-a-number (NaN) items, therefore not requiring any kind of mitigation measure for missing values. Prior to the ML training phase, we identified the dataset outliers, defined as the values outside the physiological ranges for each variable. After outlier removal, resulting missing data were imputed using the multiple imputation by chained equation (MICE) method. As highlighted by randn.Given the relatively low number of subjects involved in the study, and in order to comply with the basic “rule of thumb” ,22 applicaret package [caret package in order to provide a reliable comparison between the different models using the same training strategy, the same seed for splitting data into a training and test set and the same conditions for training the net.With the restructured dataset, we drafted and trained five different ML models, all of them supervised, which are briefly reported below. All the models were implemented using the R-based  package , a powerPrior to the model training, the dataset, composed of 23 variables, including the outcome, and 228 observations, was randomly divided into a fully independent training and test set, with a percentage of 90 and 10% of data, respectively. A 10-fold cross validation was employed in order to obtain robust data with respect to eventual overfitting phenomena .The models were compared in terms of regression capability according to the root mean square error (RMSE) and to the R-squared, calculated over the test set  with respect to the outcome, and for each ML algorithm, the best model selected was not the one with the lowest RMSE or R-squared, but the simplest acceptable one, represented by the simplest model within one standard error from the lowest RMSE. This choice was performed under two main principles: (i) in order to cope with the trade-off between simplicity and accuracy of the model, and (ii) to further avoid overfitting issues that could eventually decrease the generalizability of the model.The least absolute shrinkage and selection operator, mostly known as LASSO, represents a regression analysis method, often used in the ML framework, performing both variable selection and regularization aimed at enhancing the prediction accuracy and interpretability of the resulting model. Introduced in the ML universe by Tibshirani , it becoRidge regression is a widely used technique for analyzing multiple regression data severely affected by multicollinearity problems . If multMerging characteristics of both LASSO and RIDGE methods, the elastic net seeks to put together the advantages of both techniques making a blend of them . Its maiClassification and regression trees (CART) are useful and commonly used ML models, based on the deconstruction of the overall sample into smaller groups, performed through repeated, binary splits of the patient sample, considering one exploratory variable at a time .Their advantages are manifold, including the ease of adaptation to different data, including cross sectional, longitudinal, survival data, the possibility to use different types of response variables, and the fact they do not need to make any assumptions in terms of the normality of the data distribution. The main limitations of CART models include their sensitivity to data changes and their somewhat limited interpretability.Random forest (RF) are learning methods particularly useful for classification and regression, operating by building up a series (forest) of decision trees at the training and outputting the class that is the mode of the classes, for classification, or the mean prediction, for regression, of the individual trees .With respect to the classical decision trees, RF represent an improvement in terms of overfitting issues for the training set. They carry on several advantages, including the performance of implicit on-the-run feature selection, the provision of accurate indicators of feature importance, the absence of need for particular data preparation prior to the application of the ML model, the opportunity for them to handle binary, categorical, numerical features without any need for scaling, normalization or standardization. They are also relatively quick to train and versatile, although their interpretability is often cumbersome.The five ML methods mentioned above were compared in terms of prediction accuracy, using the RMSE as the main evaluation metrics.The results obtained are displayed in caret package relying on 500 trees, has the best performances, outperforming the other classifiers, three of which  display very similar error values performing the regression task.As displayed, the random forest, which is trained by the R-based However, the models were also evaluated depending on other parameters, including the time elapsed for the full training of the regressor, the memory used, and the number of variables included within the model (out of the 22 variables available within the dataset inputs).n = 7), making it useful also as a predictive tool for the clinician.The random forest model when trained achieved the best performances using a relatively low number of variables : (i) total lung capacity (TLC); (ii) mean nocturnal basal impedance at 3 cm (MNBI3); (iii) diffusing capacity for carbon monoxide (DLCO); (iv) forced expiratory volume in the first second (FEV1); (v) forced vital capacity (FVC); (vi) mean nocturnal basal impedance at 5 cm (MNBI5); (vii) mean nocturnal basal impedance at 7 cm (MNBI7).caret package used for training allows building up the random forest based on 500 trees, but the result obtained suggests an overall stabilization of the RMSE already at around 150 trees, suggesting that even simpler models, with respect to the one used for the present investigation, would enable a similarly precise regression given the inputs of the present dataset. Therefore, although the employment of the caret package was aimed at comparing the different classifiers, other R-based packages, allowing the use of simpler classifiers, can be applied in case of computational constraints eventually occurring.As mentioned above, the ILD is the leading cause of death in patients with SSc. Lung fibrosis is present in 80% of patients with SSc; among them, 25–30% develops a progressive ILD. ILD generally presents during the first 4–6 years after the onset of scleroderma ,32,33. SWith respect to the majority of published works, our data were extracted by a single dataset, thus avoiding possible “batch effects” due to different data sources for the training and test set. Obviously, as SSc is a rare disease, whose incidence accounted for 7.2–33.9 cases per 100,000 individuals in Europe , it is rIn terms of ML, the application of supervised algorithms was methodologically needed due to the presence of a known output driving the algorithm to learn the possible input-output associations. Overall, one of the main limitations of our study is represented by the small number of patients included in the dataset. Indeed, despite having applied a resampling method with random observations added to the dataset, it is essential to report that ML algorithms are more efficient when a high number of data are available for training and testing. Future works should then make profitable use of larger datasets for this purpose.caret, including the tidymodels library, would allow the data scientist to reduce the complexity of the classifier, in turn saving time and computational resources in constrained use cases.From the model’s point of view, taking into account their pros and cons, random forest was seen to ensure good performances in terms of prediction error, performing the regression task on a relatively low number of variables, making the overall model simple enough to be used by the clinician. However, its higher computational burden with respect to the other models make it poorly usable in cases where fast response times are requested, or where computational load might represent a significant constraint. In this regard, once established that the model owns optimal properties in terms of correct classification (or regression) with respect to other methods, the usage of R-based packages and libraries other than The present work was carried out investigating a small cohort of subjects with SSc and attempted to predict early lung involvement according to clinical and instrumental tools via the application of ML models. According to the results obtained, ML models can be used for predicting early lung involvement in SSc patients. Thanks to this approach, we found that spirometry parameters could predict ILD in our cohort. This was even more accurate if used along with impedance pH monitoring. Risk-free and sensitive screening methods are needed for early detection of lung involvement in SSc patients and ML could be the answer to this question in the future: indeed, ML could help to diagnose interstitial lung disease in SSc patients in early stages and could be a useful tool to identify the patients who may need early therapy, improving their quality of life and reducing hospitalizations or unnecessary exams, with a consequence of saving money for the national health systems and burden reduction for the patients. In addition, future studies can be performed applying ML to classify SSc with respect to other autoimmune disorders or medical conditions with somewhat similar clinical characteristics.


Nowadays, the average human life expectancy is increasing. This applies to both healthy and chronically ill people. It is possible due to improvements in technology, living conditions, and better, more accessible medical care. As the number of patients with end-stage organ failure increases and due to great progress in modern transplantology, every year the number of transplantations rises worldwide. Organ transplantation is not only an ultimate form of therapy but also, especially nowadays, a life-saving procedure. Patients who have undergone transplantation need to face the problem of long-term immunosuppressive therapy on a daily basis, which prolongs the proper function of the grafted organ and prevents the development of graft-versus-host disease. On the other hand, numerous side effects are associated with the usage of these medicaments, among these are disturbances in sex-related hormones, therefore influencing fertility.The rising need for treatment of end stage of organ failure results in an increased number of graft recipients yearly. The most commonly transplanted organs are kidney, heart, liver, bone marrow, lung and skin. The procedure of transplantation saves and prolongs the lives of chronically ill patients or at least improves the quality. However, following transplantation recipients must take immunosuppressive drugs on a daily basis. Usually, the immunosuppressive therapy comprises two or three drugs from different groups, as the mechanism of their action varies. Although the benefits of intake of immunosuppressants is undeniable, numerous side effects are associated with them. To different extents, they are neurotoxic, nephrotoxic and may influence the function of the reproductive system. Nowadays, when infertility is an urgent problem even among healthy pairs, transplant recipients face the problem of disturbance in the hypothalamic−pituitary axis. This review will provide an overview of the most common disturbances among the concentration of sex-related hormones in recipients of both sexes at different ages, including sexually immature children, adults of reproductive age as well as elderly women and men. We have also focused on the numerous side effects of immunosuppressive therapy regarding function and morphology of reproductive organs both in males and females. The current review also presents the regimen of immunosuppressive therapy and time since transplantation. Due to the great progress in immunology, pharmacology and surgery in the last decades of the 20th century, a rising number of patients can benefit at present from the wider and better results of modern transplantology. Each year, the number of graft recipients increases worldwide. For obvious reasons, this results from increasing demand, however it has become possible due to the simultaneous development of modern, cutting-edge techniques in surgery and the rising quality of postoperative treatment as well as the higher effectiveness of immunosuppressive drugs . The majThis paper focuses on the description and summary of only the latest scientific reports of the past 20 years regarding the sex hormone profile and disorders associated with the reproductive system in transplant recipients undergoing different posttransplant conditioning. Taking into account the availability of literature, the most frequently transplanted organs in last 20 years are as follows: kidney, liver, bone marrow and hematopoietic stem cells (HSC), heart.The final stage of kidney failure frequently leads to moderate or severe sexual dysfunction . The imbAccording to the latest data, the physiological levels of sex hormones are restored approximately six months after successful kidney transplantation, as uremia is not observed then anymore ,12,15. OWhen discussing the influence of kidney transplantation in the spectrum of hormonal balance, attention should be paid to the period of time following transplantation. As mentioned above, the hormonal balance should be restored approximately 5–6 months after successful transplantation. On the other hand, the influence of immunosuppressive therapy should not be omitted. The literature available provides information from different periods following transplantation, therefore all the data may be divided into the short- or long run categories.In the study of Teng  the grouThe disorders regarding the bone structure and metabolism parameters were also observed in grafted men whose immunosuppressive therapy included cyclosporin A, azathioprine and prednisone. Although, the normal concentration of T in blood was maintained, the decreased volume and wall thickness, reduced number of osteoblast and osteoclast, decreased osteoid and mineralizing surface as well as reduced appositional rate were frequently diagnosed ,18. PerhThere are studies which evaluate the long-term influence of immunosuppressive therapy including cyclosporin A, tacrolimus, azathioprine and mycophenolate mofetil, in kidney-grafted men of various ages, ranging from young, middle-age to older men ,20. A diAlthough adequate recovery of sexual/reproductive function is usually revealed approximately six months after transplantation, it is not infrequent for hypothalamic-pituitary-gonadal axis inhibition to persist. Perhaps, it depends on the regimen of immunosuppressive drugs that is administered to patients following transplantation. It is not surprising that immunosuppressive treatment influences steroidogenic pathway. What is interesting, glucocorticoids are known to suppress GnRH release, and it was mirrored by the research of Tauchmanova et al. and Teng et al. ,20 whereSirolimus is nowadays believed to be one of the most harmful immunosuppressive drugs to the reproductive system. In terms of this fact, the latest reports on the influence of sirolimus on sex-related hormones in kidney-grafted men seems to be confusing. In transplanted men, inhibition of T secretion was observed frequently under such immunosuppressive therapy ,25,26. SIn modern immunosuppressive treatment, immunoglobulins, for instance basiliximab, are used by renal transplant recipients quite rarely. However, among the men of reproductive age on such a therapy, six months after surgery, the proper secretion of T was restored. On the other hand, the concentration of FSH and LH increased, suggesting an impairment in the hypothalamic-pituitary-gonadal axis. Moreover, grafted patients complained about infections, anemia, posttransplant diabetes, cholesterolaemia, triglyceridemia and hypertension, of various intensity levels and occurring with different frequency . ComparaIn the long term, immunosuppressive therapy in grafted females, especially of reproductive age, most often a multidrug regimen including cyclosporin A/tacrolimus, azathioprine/mycophenolate mofetil and prednisone is applied, as these immunosuppressive drugs are believed to be relatively safe for embryo and fetus in case of pregnancy. However, the literature reveals a significant decrease in the concentration of E2, as well as an increased level of FSH in the blood of such patients ,17. AddiThere are some studies available which indicate that steroidogenesis in kidney-grafted women under immunosuppressive therapy may be strongly affected. In patients with stable graft function a few years after transplantation, the regimen may be changed in comparison to the one applied right after the transplantation. There are indications to reduce the dose and the number of immunosuppressive medicines included in the treatment protocol. Most often, patients with stable kidney function use calcineurin inhibitors as these immunosuppressive drugs are believed to be relatively safe for recipients. On the other hand, cyclosporin A and tacrolimus have been seen to interfere with estradiol binding to the estrogen receptor when their concentration is high . Within Analogous research, as abovementioned was performed on postmenopausal women, and what was surprising, no hormonal imbalance was observed in this group of patients. Nevertheless, patients complained about the same sorts of disorders as premenopausal women with diagnosed hormonal imbalance . It woulThere are a few studies in which the influence of particular immunosuppressive therapy is not considered, instead, the authors compare the hormone profile of grafted patients with the dialyzed patients with CKD. For instance, Grossmann  revealedMost commonly noticed hormonal changes in male and female kidney-transplant recipients undergoing various regiment of immunosuppressive drugs described in the current chapter are presented in All the references cited in the current chapter are presented in the Nowadays, men constitute approximately 66% of all liver transplant recipients. It is important, since male patients suffering from end-stage of liver disease exhibit worse sexual function which is mirrored in hypogonadism and feminization. Among others, in these patients, testicular atrophy, decreased T level, reduced secondary sexual characteristics, muscle reduction, gynecomastia, decreased libido and fertility are frequently reported ,30. AccoThe data concerning the sex hormone profile in liver grafted women are scarcely found. This may be related to the fact that women constitute only one third of all liver transplant recipients. Nevertheless, successful liver transplantation in women, restores menstrual function, among others, therefore improving life quality . The obsMost commonly noticed hormonal changes in male and female liver-transplant recipients undergoing different regiment of immunosuppressive drugs described in the current chapter are presented in All the references cited in the current chapter are presented in the For over twenty years a great improvement in the treatment of numerous hematologic malignancies and aplastic anemia has been observed in modern hematology. This new mode of treatment is bone marrow transplantation. Since life expectancy of patients after transplantation is longer, attention has been paid increasingly to the quality of their lives in the long run. Bone marrow recipients frequently suffer from endocrine disturbances and these disorders may reflect in decreased fertility . GonadalMost commonly noticed hormonal changes in male and female bone-marrow-transplant recipients undergoing various regiment of immunosuppressive drugs described in the current chapter are presented in All the references cited in the current chapter are presented in the In the latest literature available, still little is known about the sex-related steroids in patients after cardiac transplantation. The study of Fleischer et al.  seems toMost commonly noticed hormonal changes in male and female cardiac-transplant recipients undergoing various regiment of immunosuppressive drugs described in the current chapter are presented in The comparison of the most commonly used regimens of immunosuppressive treatment used by the patients included in the current manuscript is presented in All the references cited in the current chapter are presented in the Without doubt, the impairment of hypothalamic-pituitary-gonadal axis in grafted patients is multifactorial. Taking into account the latest data, the proper function of both male and female gonads are usually improved approximately 5–6 months after successful transplantation. However, immunosuppressive therapy, administered daily, can adversely influence the homeostasis affecting restored gonad function. Therefore, it still remains unclear whether transplantation improves sexual and reproductive functions or not, especially in the long run. Nevertheless, in all patients after successful surgery, the sex hormone profile should be evaluated regularly, so that if any meaningful irregularities are revealed, appropriate replacement therapy can be implemented. It seems to be especially important for female patients of reproductive age, due to maternal readiness. Regardless of the percentage of transplanted females with preserved normal ovarian function, it seems to be of great importance to monitor them in order to select the most suitable contraception and family planning . On the Concluding, clinicians need to consider all the advantages and disadvantages prior to the selection of a particular immunosuppressive drug to be applied in the protocol for grafted patients, especially in the long run, as side effects may accumulate and intensify over time.


Gold compounds started to play an important role in modern medicine after the discovery of the efficacy of some gold salts against tuberculosis strains by Robert Koch . In the in vitro antiproliferative properties of auranofin against cancer cells  and gold(III) complexes were prepared, such as those stabilized by phosphines or by nitrogen donors, that were found to induce important anticancer effects both  in vivo . Thanks  in vivo . Moreove in vivo .Although the ferment that animates the scientific community on the investigation of gold-based drug candidates, the real and entire picture of the involved mechanisms and modes of action for these compounds remains largely undepicted.To deepen the knowledge on the gold-based complexes, this Research Topic encloses some fundamental contributions from worldwide outstanding researchers working in this field. In particular, the areas covered range across the synthesis and characterization of new gold N-heterocyclic carbenes (Au-NHCs), to the study of protein metalation processes, to the discovery of new mode-of-action, and up to the search of unexplored molecular targets.Tolbatov et al. described an integrated experimental and theoretical study on the reactivity of AF and its iodide derivative (AF-I) toward relevant amino acid residues or their molecular models, such as the histidine, cysteine, methionine, and selenocysteine, that may represent the possible binding sites. Interestingly, the energetic barriers for the bond formation between the gold compounds and the targets have been calculated through computational methods. The obtained results pointed out that the replacement of the thiosugar moiety with iodide significantly affects the overall reactivity toward the selected targets, contributing to enhance the antitumoral activity of AF-I compared with AF.In the furrow of the research on the forefather of gold-based compounds, namely auranofin, Massai et al. to the study of protein metalation by a selected panel of Au(III) complexes. These compounds were reacted with two representative proteins, i.e. human serum albumin and human carbonic anhydrase I, and with the C-terminal dodecapeptide of TrxR. ESI-MS analysis permits to elucidate the nature of the resulting metal–protein adducts from which the main features of the occurring metallodrug–protein reactions can be inferred. In some cases, MS data have been integrated with other independent biophysical measurements for a comprehensive description of the occurring processes.A very informative analytical technique such as the high-resolution ESI mass spectrometry, has been successfully applied by Radisavljević and co-workers summarized in their review the chemistry of some mononuclear and polynuclear gold(III) complexes. In particular, a special description has been deserved for gold(III) complexes with nitrogen-donor inert ligands and their kinetic behavior toward different biologically relevant nucleophiles. Mechanisms of interaction with DNA, serum albumin, and cytotoxic activity have been thoroughly discussed also in the light of computational calculations.Because of their oxidizing character, Au(III) complexes are considered an interesting and promising class of potential anticancer compounds involving, beyond the protein metalation, probably also the oxidative cell stress. Tong et al. in their review have masterfully summarized the efforts spent in the last years not only on the study of Au(III)-NHC, but also on porphyrin and pincer-type cyclometalated gold complexes. From this description, emerge the anticancer properties of gold(III) compounds and the identification of molecular targets involved in the mechanisms of action. Moreover, particular attention has been devoted to the chemical formulation strategies that have been adopted for the delivery of cytotoxic gold compounds, and for ameliorating the in vivo toxicity.To date, a great number of different structures of gold compounds have been investigated for their anticancer properties and, among these, Au-NHCs hold great potential. It has been demonstrated that the antiproliferative effects of several gold NHCs were related to their antimitochondrial effects associated with potent inhibition of TrxR. Galassi and coworkers. They performed enzymatic assays on the inhibition potential of the studied compounds toward the dihydrofolate reductase (DHFR), an enzyme involved in metabolic pathways crucial for cancer cell’s growth and survival and overexpressed in tumor cells. The results have been compared to those obtained for TrxR, the most recognized molecular target for gold compounds.Another class of drug candidates, i.e., imidazolate phosphane gold(I) compounds, has been studied by Yue et al., that summarizes the complex relationship between various gold derivatives and the immune system. Gold complexes seem to reverse tumor immune escape and directly facilitate the functions of immune cells, leading to enhanced anticancer effects. In particular, the paper described the antitumor effects of gold drugs and their relationships with various aspects of antitumor immunity, including innate immunity, adaptive immunity, immunogenic cell death, and immune checkpoints, as well as their roles in adverse effects.As completion of this Research Topic’s overview, the role of gold compounds in anticancer immunity has been elucidated in a review by This Research Topic aims to give to the readership a new point of view on the current research on gold-based drug candidates, covering different aspects, from the synthesis of new molecules to the study of their relationship with biomolecular targets and the immune system. As Guest Editors, we believe that this collection could be useful to disseminate the last advancements in the research of gold anticancer drugs.


Ponte et al.). Across the vertebrate tree, agnathans (lamprey) occupy the base representing intriguing models to understand early brain evolution in vertebrates. Remarkably, lamprey display complex neuropeptidergic systems and essential components of neuronal communication in the animal brain controlling and regulating several conserved behaviors, such as appetite. As an example, galanin, a neuropeptide known to regulate many physiological processes, including feeding and nociception in mammals, displays a wider expression pattern in the larval brain which is restricted to the ventral pallium, lateral hypothalamus, and prethalamus in the adult brain of sea lamprey Petromyzon marinus . Neuropeptidergic systems controlling food intake behavior are among the most studied in teleost fish, due to the high degree of conservation in vertebrates and the relevant impact in aquaculture , a teleost species providing the unique opportunity for studying vertebrate genome evolution after an autotetraploid whole genome duplication over a period that is long enough to reveal long-term evolutionary patterns, but short enough to give a high-resolution picture of the process .Aquatic species have served as models in brain evolution to address questions on the origin of the nervous system for a long time. The aquatic environment and its inhabitants have offered the possibility to understand how animals progressed from a simple nerve net to a complex centralized nervous system . We have already learnt much about vertebrate brain evolution from the comparative neurobiological approach relying on embryonic gene expression and mature neuroanatomy, with emphasis also on brain asymmetries and lateralization . The combination of neuroanatomical and behavioral analyses, imaging, and cutting-edge molecular genetic techniques represents a powerful approach to investigate gene-by-environment interaction effects, how genetically encoded asymmetry may change across the lifespan, and how anatomical asymmetries are linked to behavior. Among teleost fish, zebrafish at both the larval and adult stages, are extensively used in central nervous system research by targeting various brain disorders . Identification and combination of molecular markers for a specific Ca2+ store and its neuronal-type association are accurately reported in the adult zebrafish brain, where calsequestrin, a calcium binding protein, is localized on the neuronal endoplasmic reticulum . Remarkably, the two isoforms identified (Casq1 and Casq2) are differentially localized in the zebrafish brain with virtually no overlapping. In addition, they are helpful to understand adaptive neuronal function to the aquatic habitat. Moreover, zebrafish are a well-established in vivo model for investigating synapses within the elaborate architecture of neurons. Pieces of evidence have been discussed on the cell biological mechanisms that develop, maintain, and regulate electrical synapses and mechanistic relationships between electrical and chemical synapse formation . In conclusion, neuroscientists will find useful information regarding the brains of aquatic species, and how understanding these features contributes to our understanding of brain evolution, hopefully leading to further important discoveries in both aquatic and non-aquatic neurosciences.Studies of the teleost brain have contributed greatly toward our understanding of the processes of brain evolution and how environmental factors, such as sensory experience, modulate brain region sizes (PG, J-PB, and LD'A contributed to the whole conception. LD'A wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.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.


Multivariate ordinal regression model adjusted for sex, age, and educational level indicated that HS and SMR patients have three and five times more chances of having a lower quality of life than healthy volunteers . There was no association between complications of HS disease and quality of life scores. In contrast, worse quality of life was observed in SMR patients that presented back or leg pain, leg paresthesia, and bladder dysfunction. In conclusion, HS and SMR significantly impact the overall quality of life of the affected individuals, reinforcing the importance of efforts to control and eradicate this debilitating disease and suggesting that multidisciplinary clinical management of schistosomiasis patients would be more appropriate and could potentially improve patient's quality of life.Schistosomiasis is a major public health problem in tropical areas of the world. Health-related quality of life (HRQOL) measurement is being widely used to evaluate the impact of a disease or treatment in several aspects of daily life. However, few studies evaluated the impact of severe forms of schistosomiasis on HRQOL of affected individuals and compared them to healthy controls with a similar socio-demographic background. Our aims were to evaluate the HRQOL in patients with hepatosplenic schistosomiasis (HS) and schistosomal myeloradiculopathy (SMR) and healthy volunteers (HV) and determine if clinical complications of the disease are associated with HRQOL scores. We interviewed and evaluated the HRQOL in 49 patients with HS, 22 patients with SMR, and 26 HV from an outpatient clinic of the Federal University of Minas Gerais University Hospital using the WHOQOL-BREF questionnaire. SMR and HS patients had a significantly lower overall quality of life score when comparing with the HV control group ( Schistosoma mansoni, and over 25 million individuals are at risk of infection  measurement is being widely used to evaluate the impact of a disease or treatment in several aspects of daily life , 13. AssS. mansoni infection  and fully conducted according to the guidelines in the Declaration of Helsinki from the World Medical Association . All patS. mansoni contaminated freshwater, serological tests, examination of cerebrospinal fluid, clinical evidence of spinal cord injury confirmed by magnetic resonance of the lumbar spine and differential diagnosis to exclude other causes of myelitis   and with schistosomal Myeloradiculopathy (SMR) previously diagnosed and currently receiving medical care at Orestes Diniz Infectious and Parasitic Diseases Treatment Center, an outpatient clinic of the Federal University of Minas Gerais University Hospital . The caregivers accompanying patients to their clinic appointment served as non-infected controls and were included in the healthy volunteer group (HV). The sample size was calculated based on a pilot study conducted with 10 volunteers from each group  that indicated a minimum sample size 21 of participants for each study group, considering a 95% two-sided confidence level and 80% power. Adult individuals (18–65 years old) of both genders that fit the inclusion criteria for each group were invited to participate in the study. The following exclusion criteria were applied: individuals diagnosed with other infectious diseases, other liver diseases, other forms of myeloradiculopathy, and noticeable memory loss. HS group consisted of 49 adult patients, of both genders, with a previous hepatosplenic schistosomiasis diagnosis based on parasitological stool test (PST), rectal biopsy, liver biopsy serological tests and ultrasonography of the abdomen and upper digestive endoscopy. For the SMR group, 22 adult patients, of both genders, with a previous diagnosis of SMR based on PST, history of contact with therapy) , were inAll participants were interviewed on the day of their routine appointment at the outpatient clinic and answered a clinical-socio-demographic questionnaire and the WHOQOL-BREF questionnaire, the shortened version of the World Health Organization Quality of Life questionnaire (WHOQOL-100) . The WHOThe data collected was stored in a computerized database using Excel software (Microsoft Office 2013) and analyzed using the Statistical Package for Social Sciences software (SPSS), version 20.0 . Significance was accepted at the 0.05 level. Frequency distribution tables were constructed, and central tendency and variability measures were calculated for the total sample and for each study group. Kolmogorov-Smirnov normality was used to determine if the variables have a Gaussian distribution. Categorical variables were compared using Pearson's chi-square or exact Fisher test, and the numerical variables using the Kruskal-Wallis test. For multiple comparisons among groups, Mann-Whitey test with Bonferroni correction was used. The proportional odds logistic regression model was used to estimate the odds ratio with 95% confidence intervals.The socio-demographic data of the study population are depicted in p = 0.007). There were no statistical differences among groups when the physical, environmental, social, and psychological domains of WHOQOL-BREF were evaluated. Multiple comparison analysis demonstrated that SMR or HS had a significantly lower overall quality of life score when comparing with the HV group . Although SMR had a lower overall quality of life score when compared to HS, this difference was not statistically significant (p = 0.363). Further analysis using the multivariate ordinal regression model and adjusting for sex, age, and educational level indicate that HS and SMR patients have three and five times more chances of having a lower quality of life than healthy volunteers , they observed that infection with S. mansoni reduced the overall quality of life of individuals by 16 points when compared to non-infected individuals, thus reinforcing that schistosomiasis have a significant impact on the quality of life of individuals (Furst et al.  investigividuals . In our In China, studies that used the EQ-5D plus questionnaire indicated that chronically infected patients with S. japonicum also had low quality of life scores and heavy disability weights that are associated with age, impaired work capacity, depression, anxiety, ascites, and active hepatitis B infection , 17. In In Brazil, Barbosa and Pereira da Costa , 35 evalS. mansoni infection” was associated with lower scores of overall HRQOL.Nascimento et al.  conducteThis study indicated that HS and SMR patients had a higher chance of having a worse quality of life. However, our results should be taken with caution. The non-infected control group consisted of caregivers accompanying patients receiving medical care at our outpatient clinic. Although we observed significant differences among patients and non-infected controls, healthy volunteers also reported low scores of HRQOL. Cruz et al.  previousS. mansoni in rural areas (Some of the differences observed in the socio-demographic variables among the different groups are due to the inherent characteristics of the disease forms or related to the participants' professional occupation. HS patients are usually older than patients with other forms of schistosomiasis because severe liver fibrosis and portal hypertension take a long time to develop, and it usually requires multiple infections , 11. Symal areas , 9. The In conclusion, our results indicate that HS and SMR significantly impact the overall quality of life of the affected individuals, reinforcing the importance of efforts to control and eradicate this debilitating disease and suggesting that multidisciplinary clinical management of schistosomiasis patients would be more appropriate and could potentially improve patient's quality of life.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Federal University of Minas Gerais Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.SR, TP, and JL designed the study, supervised patient recruitment, performed statistical analysis and wrote the manuscript. SR, GV, and JC recruited patients, performed the analytical tests, collected the data. All authors critically revised the manuscript and approved the final submission.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.


Investigations of transparency, reproducibility and replicability in science have been directed largely at individual studies. It is just as critical to explore these issues in syntheses of studies, such as systematic reviews, given their influence on decision-making and future research. We aim to explore various aspects relating to the transparency, reproducibility and replicability of several components of systematic reviews with meta-analysis of the effects of health, social, behavioural and educational interventions.The REPRISE (REProducibility and Replicability In Syntheses of Evidence) project consists of four studies. We will evaluate the completeness of reporting and sharing of review data, analytic code and other materials in a random sample of 300 systematic reviews of interventions published in 2020 (Study 1). We will survey authors of systematic reviews to explore their views on sharing review data, analytic code and other materials and their understanding of and opinions about replication of systematic reviews (Study 2). We will then evaluate the extent of variation in results when we (a) independently reproduce meta-analyses using the same computational steps and analytic code (if available) as used in the original review (Study 3), and (b) crowdsource teams of systematic reviewers to independently replicate a subset of methods  in a sample of the original reviews; 30 reviews will be replicated by 1 team each and 2 reviews will be replicated by 15 teams (Study 4).The REPRISE project takes a systematic approach to determine how reliable systematic reviews of interventions are. We anticipate that results of the REPRISE project will inform strategies to improve the conduct and reporting of future systematic reviews.The online version contains supplementary material available at 10.1186/s13643-021-01670-0. Many researchers have expressed alarm at the variation in results of systematic attempts to come up with the same answer to the same research question . There hA reproduction or replication of an original systematic review might yield different results for various reasons. For example, authors of an original review might have made errors throughout the review process, by failing to include an eligible study, or entering study data incorrectly in a meta-analysis. Alternatively, different results might arise due to different judgements made by review teams about how best to identify studies, which studies to include, which data to collect and how to synthesise results –23. UndeThe few previous investigations of the transparency, reproducibility, and replicability of systematic reviews and meta-analyses differ in scope. Some have evaluated transparency of published reviews, documenting how often systematic reviewers report methods completely , or share review data, analytic code, and other materials e.g., –30). Som. Som30])How frequently methods are reported completely, and how often review data, analytic code and other materials  are made publicly available;Systematic reviewers’ views on sharing review data, analytic code and other materials and their understanding of and opinions about replication of reviews;The extent of variation in results when independently reproducing meta-analyses using the same computational steps and analytic code (if available) as used in the original review; andThe extent of variation in results when replicating the search, selection, data collection and analysis processes of an original review.Available research on the transparency, reproducibility and replicability of systematic reviews leaves many questions unanswered. We do not know the extent to which completeness of reporting is associated with replicability of systematic reviews. It is unclear to what extent factors such as journal policies are associated with sharing of data, analytic code and other materials in systematic reviews, and what facilitators or barriers exist towards reviewers adopting them. We do not know what stages of the systematic review process, such as the search, selection, data collection or synthesis, are most prone to discrepancies between an original and replicated review. To address these gaps, we aim to explore various aspects relating to the transparency, reproducibility and replicability of several components of systematic reviews with meta-analysis of the effects of health, social, behavioural and educational interventions. Specifically, the objectives of the project are to evaluate in a sample of systematic reviews of interventions:The REPRISE (REProducibility and Replicability In Syntheses of Evidence) project consists of a suite of studies to address our four objectives Fig. . We willWe will focus on systematic reviews of the effects of health, social, behavioural and educational interventions. Eligible interventions will include any intervention designed to improve health , promotThe objective of this study is to evaluate the completeness of reporting and sharing of review data, analytic code and other materials  in systematic reviews with meta-analysis. We will do this by conducting a cross-sectional evaluation of systematic reviews published in 2020.Written in English, indexed in the most recent 1-month period closest to when the search for the present study is run, in one of the following bibliographic databases in the health and social sciences: PubMed, Education Collection via Proquest, Scopus via Elsevier and Social Sciences Citation Index and Science Citation Index Expanded via Web of Science;Includes randomised or non-randomised studies (or both) evaluating the effects of a health, social, behavioural or educational intervention on humans;Lists the references for all studies included in the review; andPresents at least one pairwise meta-analysis of aggregate data, including at least two studies, using any effect measure .We will include a random sample of completed systematic reviews with meta-analysis in our evaluation. To be considered a “systematic review”, authors will need to have, at a minimum, clearly stated their review objective(s) or question(s), reported the source(s) (e.g. bibliographic databases) used to identify studies meeting the eligibility criteria, and reported conducting an assessment of the validity of the findings of the included studies, for example via an assessment of risk of bias or methodological quality. We will not exclude articles providing limited detail about the methods used (e.g. articles will be considered eligible if they provide only a list of the key words used in bibliographic databases rather than a line-by-line Boolean search strategy). Systematic reviews with meta-analysis meeting the following additional criteria will be eligible for inclusion in the study:Using search strategies created by an information specialist (SM), we will systematically search each database listed above for systematic reviews with meta-analysis meeting the eligibility criteria. For example, we will run the following search in PubMed:  AND 2020/11/02:2020/12/02[EDAT]. Search strategies for other databases are available in Additional file Reported the complete line-by-line search strategy used for at least one (or for each) electronic database searched;Reported the process for selecting studies, collecting data and assessing risk of bias/quality in the included studies;Presented the summary statistics, effect estimates and measures of precision  for each study included in the first meta-analysis reported in the review; andMade data files and analytic code publicly available, and if so, specified how to access them.Two investigators will independently and in duplicate collect information about each systematic review using a standardised data collection form. Any discrepancies in the data collected will be resolved via discussion or adjudication by another investigator. Prior to data collection, both investigators will pilot test the data collection form on a random sample of 10 systematic reviews within the set of 300, discuss any discrepancies and adjust the form where necessary. The form will include items capturing general characteristics of the review  and items that characterise, for example, whether systematic reviewers:We will evaluate the main systematic review report, any supplementary files provided on the journal server or in a public or institutional repository, or the review protocol if the authors specify that the relevant information is contained therein. The wording of items will be identical to that used in previous evaluations of this nature , 39 to aCochrane Database of Systematic Reviews, Campbell Systematic Reviews, JBI Evidence Synthesis) versus published elsewhere; between the 2020 reviews of health interventions and a previously examined sample of 110 systematic reviews of health interventions indexed in MEDLINE in February 2014 )The REPRISE project should inform strategies to improve the conduct and reporting of future systematic reviews. With the production of systematic reviews and meta-analyses increasing exponentially , 67 and Additional file 1:. Search strategies


Coffee production is a global industry with roasteries throughout the world. Workers in this industry are exposed to complex mixtures of gases, dusts, and vapors including carbon monoxide, carbon dioxide, coffee dust, allergens, alpha-diketones, and other volatile organic compounds (VOCs). Adverse respiratory health outcomes such as respiratory symptoms, reduced pulmonary function, asthma, and obliterative bronchiolitis can occur among exposed workers. In response to health hazard evaluations requests received from 17 small- to medium-sized coffee facilities across the United States, the National Institute for Occupational Safety and Health conducted investigations during 2016–2017 to understand the burden of respiratory abnormalities, exposure characteristics, relationships between exposures and respiratory effects, and opportunities for exposure mitigation. Full-shift, task-based, and instantaneous personal and area air samples for diacetyl, 2,3-pentanedione and other VOCs were collected, and engineering controls were evaluated. Medical evaluations included questionnaire, spirometry, impulse oscillometry, and fractional exhaled nitric oxide. Exposure and health assessments were conducted using standardized tools and approaches, which enabled pooling data for aggregate analysis. The pooled data provided a larger population to better address the requestors' concern of the effect of exposure to alpha-diketones on the respiratory heath of coffee workers. This paper describes the rationale for the exposure and health assessment strategy, the approach used to achieve the study objectives, and its advantages and limitations. Coffee production is a global industry with roasteries located throughout the world. Production involves receiving green (raw) beans, roasting green beans, grinding roasted beans, in some facilities flavoring roasted ground or whole beans, weighing and packaging roasted and ground, flavored or unflavored coffee, and shipping . WorkersBetween 2008 and 2012, two cases of OB were identified in coffee production co-workers exposed to flavoring chemicals . SubsequHHEs are public health responses to emerging health and safety issues in workplaces mandated by the Occupational Safety and Health Act of 1970 and the Mine Safety and Health Act of 1977, with advantages and some limitations. Their narrowed focus on a particular workplace issue facilitates in-depth investigation that can lead to a resolution of the issue that triggered the investigation, however, the information generated may not always be generalizable knowledge that can be applied more broadly for prevention. Moreover, HHE investigations are constrained by time and resources dedicated to any one investigation. In the coffee industry (North American Industry Classification System code 311920) in 2016, 93% of the establishments were small- (<20 workers) to medium-sized (≥20–<500 workers) workplaces employing 48% of the workforce  workers participated in the exposure survey and 384 (58%) participated in the health investigation. The analysis of the pooled data was approved by the NIOSH Institutional Review Board (IRB). The specific objectives of the pooled analysis were to (1) quantify full-shift, short-term task-based, and instantaneous exposures to alpha-diketones, (2) identify and quantify factors affecting short-duration and full-shift exposures to alpha-diketones, (3) characterize the respiratory health of workers including pulmonary function and symptomology, (4) evaluate exposure-response relationships with exposure metrics and surrogates such as tasks or proximity to process, and (5) evaluate emission sources and recommend exposure control options.The objective of this paper is to describe the rationale for the exposure and health assessment strategy, the approach used to achieve the study objectives, and its advantages and limitations.The investigations focused on characterizing both long-term average exposures and high-intensity, short-duration “peak” exposures to diacetyl and 2,3-pentanedione, because these exposures may be associated with small airways damage related to OB; peak exposures can potentially overwhelm the capacity of normal defense mechanisms and induce adverse health effects , 32. PeaTo understand personal exposures and characterize emission sources, both personal and area sampling was conducted for alpha-diketones . PersonaAn integral component of exposure assessment is evaluating exposure variability and understanding factors affecting exposures. Statistical modeling of exposure factors requires the collection of both exposure measurements and detailed contextual information on workplace characteristics such as: processes, control measures, environmental conditions, jobs, tasks, source materials, worker activities, and other relevant work environment factors , 36–40. In this study, collecting the desired information on exposure determinants during sampling was challenging because of limited time, staff, and resources available to conduct the assessments at each facility. Exposure assessment is a critical component of epidemiologic studies, but can present a significant challenge , 46. ManIn this study, information on jobs performed and tenure in the coffee or flavoring industry was gathered in the work history questionnaire. The exposure module elicited information on the frequency and duration of tasks performed in current job, which captures and reflects worker-specific exposure circumstances . HoweverCross-sectional surveys were conducted to investigate evidence of OB, asthma and other respiratory diseases using a combination of novel and established methods described in detail by Harvey et al. . The queThe health effects of concern in the coffee production facilities include asthma and OB, which may manifest with a range of overlapping respiratory symptoms and functional abnormalities. The objective of the health investigation was to assess the burden of respiratory abnormalities, in particular early markers of disease that could inform prevention. For instance, spirometry provides objective measures of functional abnormalities and their severity, but may be normal in early OB or mild asthma on account of insensitivity to changes in the small airways –75. The IOS is not a new technology , but morDespite these advantages, IOS does pose challenges. Normative values to aid in the interpretation of IOS parameters are not robust and available for only select small sub populations , 81. AddThe health assessment strategy, while extensive and thorough, has several limitations with some that are inherent in the nature of HHE mechanism including: (1) inability to assess longitudinal change in symptoms or lung function because of the cross-sectional nature of the study, (2) potential for healthy worker survivor effect because of enrolling current workers only, (3) potential for bias if differential participation by health status occurred as participation was not 100%, and (4) potential for underestimation of exposure and respiratory health burden in the industry as the HHE requests were often made by management at facilities without known health problems. Additionally, despite the extensive respiratory health evaluations, additional medical testing such as collecting blood samples for immune response to allergens and potential novel biomarkers of early pathophysiologic changes, radiographic imaging that may be more sensitive than lung function for small airway diseases and performing challenge testing to assess for airways hyperresponsiveness could result in better characterization of respiratory health.A variety of standard and advanced statistical models will be fit for the various outcome measures of interest with the many quantitative exposures to alpha-diketones and quantitative and qualitative metrics of task exposure surrogates. Least-square regression will be used to fit models for continuous outcomes from FeNO, spirometry and IOS parameters. Logistic regression models will be used to model polytomous outcomes from multiple categories of IOS, spirometry, asthma and subgroups identified by machine learning, and binary outcomes from symptoms, chronic disease diagnoses, and other asthma variables. All models will include adjustment for age, sex, race, body mass index, height, weight, smoking status, allergic status, and tenure as appropriate. Model with continuous exposure metrics will be evaluated for non-linearity through fitting restricted cubic splines . The varThe exposure assessment strategy facilitates several exposure metrics to be generated to explore multiple questions on the nature of the exposure-response relationships. The respiratory health outcomes include upper or lower respiratory symptoms, disease diagnoses, spirometry and IOS parameters, and FeNO values. Thus, a spectrum of adverse health effects can be explored, including those that may be related to flavoring chemicals and those that may be related to allergen and irritant exposures such as green coffee bean and dust exposures. The analyses using machine learning methods may identify underlying patterns of various health measures parameters that may represent new markers of early health effects. The various exposure-response relationships can address: (1) the relevance of peak, average, cumulative intensity or duration of exposure, (2) the role of individual or combined alpha-diketones or mixed VOC and dust exposures, and (3) the shape of the exposure-response relationship for the various health outcomes.Results of exposure modeling can identify the effects of contextual information on full-shift and task-based exposures to enable identification and prioritization of exposure mitigation options. The use of the advanced Bayesian modeling method facilitates the evaluation of all determinants that make it into the numerous (could be as high as one thousand) final models which are then averaged to summarize the importance  and effect (parameter estimate) of each variable; in traditional modeling, such decisions are made based on a single final model fit using a statistically convenient strategy of forward selection or backward elimination . The setWith any approach, there are trade-offs and limitations of selected study design or strategy. Primary limitations of exposure assessment were: (1) not measuring exposure to dust and allergens that are important for asthma outcomes (though exposure surrogate of the task of handling green beans may provide some insights), (2) difficulty in collecting adequate detail on time-varying contextual information during exposure monitoring, and (3) impracticality of collecting task duration and frequency information for historical jobs. Job titles in the coffee workplaces were often non-specific and did not clearly distinguish among workers and their tasks. Task-based sampling offers the opportunity to directly identify high exposure tasks for targeted controls, may provide more precise estimates of the long-term average exposures for epidemiologic studies under some circumstances when exposures are highly variable , 89, 90,Collecting contextual information is challenging as it entails accounting for time over which innumerable factors may change causing measured exposures to vary considerably. Collecting time-varying contextual information requires direct observation or worker-recording of tasks, duration or frequency, and other factors along the source-receptor pathway, which is challenging and time and resource intensive , 96–98. While the health assessment was extensive, a comprehensive health assessment is time and resource prohibitive and not practicable for HHEs. Additionally, some potential biases could have been minimized by including former workers and recruiting additional worksites with potentially more varied burden of respiratory disease and exposure experiences, but this was not feasible. Likewise, longitudinal follow-up study design would be ideal but not typical within the HHE Program context. Nevertheless, the combination of several tests with advanced machine learning methods holds promise for the potential identification of early markers of respiratory effects.The overall goal of the study was to characterize exposure conditions, respiratory health, and exposure-response relationships among coffee production workers, ultimately leading to exposure mitigation and prevention of adverse respiratory health outcomes. To achieve these goals, extensive exposure and health assessments were conducted within the confines of the HHE Program. Data were pooled to provide a large enough population to explore exposure-response relationships to address one of the requestors' primary concerns about the effect of exposure to alpha-diketones on the respiratory heath of coffee workers. Strengths and limitations of the approaches used are discussed. It must also be emphasized that when use of secondary data from individual HHEs is deemed to constitute human subjects research, all regulations governing human subjects research must be followed including approval from the NIOSH IRB.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.MV, KC, and JC-G contributed conception and design of the study. MV wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This work was supported by the National Institute for Occupational Safety and Health (NIOSH).The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention.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.