As of December 2009, cystic fibrosis (CF) newborn screening (NBS) is performed in all 50 US states and the District of Columbia. Widespread implementation of CF newborn screening (CFNBS) in the US and internationally has brought about new and varied challenges. Immunoreactive trypsinogen (IRT) remains the first, albeit imperfect, biomarker used universally in the screening process. Advances in genetic testing have provided an opportunity for newborn screening programs to add CFTR sequencing tiers to their algorithms. This in turn will enable earlier identification of babies with CF and improve longer-term outcomes through prompt treatment and intervention. CFTR sequencing has led to the ability to identify infants with CF from diverse ethnic and racial backgrounds more equitably while also identifying an increasing proportion of infants with inconclusive diagnoses. Using the evolution of the New York State CF newborn screening program as a guide, this review outlines the basic steps in a universal CF newborn screening program, considers how to reduce bias, highlights challenges, offers guidance to address these challenges and provides recommendations for future consideration. Newborn screening for cystic fibrosis (CF) has been available in all 50 US states and the District of Columbia since December 2009 . CF newbIn 1979, a breakthrough occurred in the early diagnosis of CF. It was noted that elevated levels of immunoreactive trypsinogen (IRT), a pancreatic enzyme precursor, could be measured using dried blood spots and were elevated in infants born with CF . DespiteGiven the limitations of IRT alone, the Wisconsin NBS program leveraged the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and modified its CF NBS algorithm in 1994, becoming the first US state to utilize a two-tier program that combined IRT measurements with DNA (deoxyribonucleic acid) testing for the most common CFTR genetic variant, F508del . With imOther states followed Wisconsin’s lead by redesigning their CFNBS programs. Massachusetts expanded the panel of CFTR variants included in two-tier testing, with resultant gains in sensitivity and the identification of more putative CF carriers . CaliforUniversal CFNBS was instituted in all US states in 2009, but states continued to vary in the extent of CF DNA analysis, with some states screening only for the single most common CFTR variant, F508del, and others adopting a more extensive CF DNA variant panel. The infeasibility of a single standard was acknowledged by the European CF Society National Screening Working Group (ECFS) who reported that variations in culture and demographics, as well as regional and country-specific health economics, made a standard newborn screening protocol unworkable .CF NBS programs have continued to examine ways of improving outcomes, such as decreasing the number of missed cases  and optiCounterbalancing concerns regarding missed cases is the goal of minimizing false-positive cases, which increases the medical burden to the health care system and emotional burden to families . Diagnostic confirmation following a positive CF NBS result is typically performed by a CF specialty care center and includes a diagnostic sweat test according to the Clinical and Laboratory Standards Institute  and CystThe New York State (NYS) CFNBS program began using an IRT/DNA algorithm in October 2002, assessing specimens from infants in the top 5% of IRT levels with an expanded CFTR panel see . A consoTo address these issues, the NYS CFNBS program changed its algorithm in 2017, adding a third tier utilizing next-generation sequencing (NGS) for any infant with one CFTR variant on the second-tier screening or with VHIRT and no CFTR variants on second-tier screening  Figure . This inThe IRT/DNA/SEQ algorithm enables identification of infants with CF with rare CFTR variants, resulting in fewer missed cases, especially among underrepresented populations, who are likely to have less well-defined CFTR variants . AdditioImproved detection of infants with CF has also identified more carriers who are not predicted to have CF . AlthougThe possibility of an inconclusive diagnosis exists within the framework of all CF newborn screening algorithms but is heightened when CFTR sequencing results are reported . DiagnosThe European CF Society’s Neonatal Screening Working Group further characterized the CRMS designation as Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CFSPID). An international panel of experts proposed the term CFSPID in 2014 as a more descriptive and clinically correct designation for this large group of asymptomatic and genetically diverse patients . The EurAdditional international efforts published in 2017 provided a global harmonization of the CRMS and CFSPID designations . The acrCurrently, such monitoring includes repeat sweat chloride testing, expanded genetic testing for the infant and parents, and other clinical tests such as fecal elastase, sputum cultures, chest X-rays and fat-soluble vitamin levels. Additional testing is decided based on the cystic fibrosis physician’s clinical judgment . AssessmIncorporation of a CFTR sequencing tier into CF NBS programs has increased identification of variants not well characterized as CF-causing. Proper identification of the clinical significance of a novel or rare CFTR variant is still an evolving area of study in medicine, with guidelines for variant classification set by the American College of Medical Genetics and Genomics (ACMG) setting the standard . In the Several public data repositories contain information about CFTR variants. The CFTR Mutation Database housed at the Hospital for Sick Kids in Toronto, Canada , maintaiIn our NY City experience, being in an urban area, we have found a multitude of challenges within our community, including the follow: 1. changes of address from the time of birth; 2. changes in surnames that are not readily noted on a newborn screening Guthrie card; 3. communication access to operational phones and computer networks for emails; 4. economic burden of lack of paid time off (PTO) in parental employment; 5. transportation difficulties to the CF center; 6. primary care setting within a clinic of multiple providers without ownership of the patient; and 7. lack of readily available interpretive phone service. These issues were heightened by the COVID-19 pandemic. It is important to create a plan as part of pandemic and disaster preparedness as such challenges are predicted to recur in the future.The lack of inclusion of rare CFTR variants in newborn screening algorithms increases the likelihood that infants from minority groups  are missed disproportionately in the newborn period , resultiNewborn screening algorithms that include NGS identify individuals with less common CFTR variants. As ivacaftor is approved for infants as young as one month of age  and elexInconclusive CFNBS results lead to a significant challenge for primary care practitioners (PCPs), who are often the first to receive notification of abnormal screens. PCPs are integral to the process of referring babies with an abnormal CFNBS result for diagnostic resolution and particularly for monitoring babies with CFSPID, who may not exhibit any symptoms in the pediatric or adolescent age groups. The importance of providing education to PCPs about recognizing symptoms that prompt rapid referral to CF centers cannot be overstated. As CFNBS algorithms change, providing clear information to PCPs is important to avoid unnecessary referrals and sweat tests. Letters of communication with PCPs regarding positive newborn screen results should use language that is concise and leaves less interpretive errors. The work of Sontag, et al. highlights the importance of strong alliance and communication between primary care physicians (PCPs), State NBS programs and local CF care and research centers .As the newborn screening landscape continues to evolve with advanced genetic technologies and changing interpretations of CFTR variants, consideration of the psychological impact to parents and families, potential fiscal impacts and ethical concerns is important. In the summer of 2021, the UK National Screening Committee commissioned a task force to elicit input from a sample of the public who had no previous knowledge of cystic fibrosis, prior to the adoption of next-generation sequencing (NGS) in CFNBS. The project aimed to determine whether making a prompt diagnosis of cystic fibrosis was important. Even when faced with an increased number of missed newborns with a CF diagnosis, the public felt that avoiding the uncertainty of a CFSPID diagnosis was just as important a goal of a CFNBS program . These fThe communication of specialty care teams with PCPs is critical in recommending the right language to convey newborn screen results and sweat testing results. This is particularly challenging when the diagnostic status of the infant remains inconclusive after sweat testing, due to the presence of one or more VUS or VCC. Multi-center and long-term studies of the psychosocial impact of a positive CFNBS result, both with or without the additional complexity of an inconclusive diagnosis, have identified parental worry and anxiety as well as concerns about increased perceptions of child vulnerability ) associaTluczek, et al. published a systematic review in 2022 synthesizing findings from 92 evidence-based, peer-reviewed research reports about psychosocial issues associated with newborn screening. The expansion of genetic variant detection will affect minoritized groups at a larger scale, requiring added support in communicating positive results, whether it pertains a true CF diagnosis or CRMS/CFSPID . The useAnother diagnostic challenge follows identification of a baby with one or more rare CFTR variants, as parental phasing is needed to determine the inheritance pattern of the variants. The process of CFTR phasing is critical in differentiating a likely heterozygote, with all variants inherited in cis from the same parent, from an infant with variants on both copies of CFTR who needs ongoing monitoring for CFSPID/CRMS. A consequence of the phasing process might be the identification of parents who have either two variants or complex alleles themselves and who are asymptomatic or mildly symptomatic . These rIdentification of CF in pregnancy raises added communication needs for interfacing with CFNBS programs . A recenSince the institution of universal newborn screening in 2009, the evolution of diagnostic methods has improved diagnosis and care of CF newborns in the US and internationally. The addition of CFTR sequencing leads to more accurate diagnosis and many positive changes for children with CF by improving nutritional status and instituting earlier interventions at specialized care centers that ultimately increase life expectancy. Although advances in genetic testing methods allow for more expansive CFTR variant identification in newborn screening algorithms, the use of NGS leads to an unintended but expected increase in the diagnosis of CRMS/CFSPID cases. Examining long-term benefits and potential psychosocial consequences for this population is an area for continued research. New York State has one of the most ethnically diverse populations in the US. The experience of the NYS CF NBS program highlighted challenges in early CF diagnosis, the expansion of the genetic variant panel, incorporation of CFTR sequencing, an increased number of inconclusive diagnoses and apparent disparities as it underwent major changes and evolved into the current IRT/DNA/SEQ algorithm. These challenges prompted quality improvement efforts and ongoing partnership between the state and specialty care centers. The continued reevaluation of our algorithm, ongoing collaboration with our state newborn screening program and commitment to the inclusion of all ethnicities may provide guidance in efforts to revise the CF newborn screening programs in other communities at the local level. At the state level, cystic fibrosis center teams are encouraged to meet with members of Department of Health newborn screening programs to continue to improve detection rates, decrease the number of false-positive tests and improve outcomes in their individual programs. In partnership with NBS laboratories, PCPs and CF care providers can aid in advocating for a more equitable CFNBS program. The implementation of third-tier sequencing, which has been successful in California and New York CFNBS models, is one approach. With highly effective modulator therapies now available in infancy, there is a new imperative for early identification and fair treatment of all babies with CF.Our goal and our hope are that medical professionals, government bodies and other decision makers work toward a more uniform approach to the early diagnosis of cystic fibrosis newborns, promoting equity, reducing harm and avoiding delayed diagnosis in all babies with cystic fibrosis.


Shared decision-making is the cornerstone of patient-centered care. However, evidence suggests that the application of shared decision-making in physical therapy practice is limited. To elicit shared decision-making and thereby potentially improve patient outcomes for patients with intermittent claudication, we developed a decision support system. This decision support system provides personalized outcomes forecasts that visualize the estimated walking distance of an individual patient. We hypothesize that personalized outcomes forecasts can support physical therapists in personalizing care to the needs and priorities of the individual patient to improve therapy outcomes.The primary aim is to evaluate the impact of personalized outcomes forecasts for patients with intermittent claudication to optimize personalized treatment. Second, this study aims to evaluate the process of implementation.KomPas, makes use of personalized outcomes forecasts, which visualize the estimated outcome of supervised exercise therapy for an individual patient with intermittent claudication. Personalized outcomes forecasts are developed using a neighbors-based approach that selects patients similar to the index patient (a.k.a. neighbors) from a large database. Outcomes to evaluate impact of implementation are patients’ functional and maximal walking distance, quality of life and shared decision-making. Process evaluation will be measured in terms of utilization efficacy, including the outcomes dropout rate and reasons to (not) use the personalized outcomes forecasts. Data will be routinely collected through two online systems: the Chronic CareNet Quality system, and the website logs of the decision support system. Additionally, observations and semi-structured interviews will be conducted with a small subset of therapists.This study uses a prospective interrupted time series (ITS) design. Participating physical therapists are divided into four clusters. Every month of the study period, a new cluster will be invited to begin using the decision support system. We aim to include data of 11,250 newly referred patients for physical therapy treatment. All therapists associated with a network of specialized therapists (Chronic CareNet) and patients treated by these therapists are eligible to participate. The decision support system, called the Formal medical ethical approval by the Medical Research Ethics Committees United ‘MEC-U’ was not required for this study under Dutch law (reference number 2020–6250). Treatment guidelines for patients with peripheral arterial disease encourage physical therapists to make shared decisions ,2. ShareIntermittent claudication is the most common symptom of peripheral arterial disease, caused by atherosclerotic narrowing of the arteries in the lower extremity. Intermittent claudication is defined as walking induced discomfort and pain in the hip and leg muscles that typically disappears after a brief rest. The recommended first treatment for these patients is supervised exercise therapy (SET) and lifestyle guidance, provided by physical therapists ,2. The dThe use of this decision support system with personalized outcomes forecasts is a novel approach in the conservative treatment of patients with intermittent claudication. Accordingly, the impact of utilizing efficacy personalized outcomes forecasts by physical therapists is unknown. The decision support system is now being implemented within the Chronic CareNet network of specialized therapists in the Netherlands , which oThe primary aim of this study is to evaluate the impact of implementing personalized outcomes forecasts  in the daily practice of physical therapists working with patients with intermittent claudication to optimize personalized treatment on the following outcomes: walking distance, quality of life, and shared decision-making, as compared to usual care. A summary of specific research questions can be found in The secondary aim of this study is to examine utilization efficacy of personalized outcomes forecasts and evaluate the implementation process  design with a parallel process evaluation  . The ITSThe personalized outcomes forecasts have been specifically developed to use in the treatment of patients with intermittent claudication by physical therapists associated with Chronic CareNet. Chronic CareNet is a network of therapists specialized in the treatment of patients with chronic non-communicable diseases, including intermittent claudication . In the All physical therapists affiliated with Chronic CareNet participate in routine data collection through the Chronic CareNet Quality system. This Quality system has been set up in collaboration with the National Database of the Royal Dutch Society for Physical Therapy (KNGF), which has gathered data of all patients with intermittent claudication treated with SET since 2015 ,19. BrieKomPas . The KomPas automatically plots the estimated therapy outcome over time, thereby making personalized outcomes forecasts easily accessible and interpretable .–14.12–14pretable .Personalized outcomes forecasts will be implemented according to the ITS design in four study clusters at equal intervals of one month. In this study, implementation involves making the personalized outcomes forecasts available for therapists to use in daily practice. Chronic CareNet comprises 55 regions (based on ZIP codes) in the Netherlands, four of which already use the personalized outcomes forecasts in the context of the pilot study and explorative study . Each stThe outcomes to determine the impact of the implementation are: 1) functional and maximal walking distance , 2) quality of life (assessed using a questionnaire) and 3) shared decision-making .Functional and maximal walking distance. Data regarding functional and maximal walking distance will be gathered through the Chronic CareNet Quality system and the personalized outcomes forecasts website. Data gathered through the personalized outcomes forecasts website are always data generated through use of the outcomes forecasts. Functional and maximal walking distance are measured by physical therapists as part of clinical daily practice, using a standardized treadmill test  [rotocol) . The tesrotocol) ,23.Quality of life. Data regarding quality of life will also be gathered through the Chronic CareNet Quality system and the personalized outcomes forecasts website. Quality of life will be assessed using the Vascular Quality of Life Questionnaire-6 (VascuQol-6). This questionnaire is the shortened version of the VascuQol-25 and is used by physical therapists as part of clinical daily practice. Questions are related to a patient’s daily activity, current symptoms, pain, and social well-being [ll-being .Shared decision-making. Shared decision-making will be measured by applying the OPTION-5 scale to audio or video recordings of clinical observations. The OPTION-5 is based on a previous 12-item measure, but more specific to the construct of shared decision-making [n-making . AssessmThe secondary aim of this study—to assess the success of implementation—will be measured in terms of uptake, or utilization efficacy . This reDropout rate. Dropout rate will be extracted from the website logs and operationalized as the percentage of patients that terminate therapy before the treatment goal is achieved. Termination of therapy is indicated by the therapist in the health record. We will also assess missing value .Reasons to (not) use the personalized outcomes forecasts. Semi-structured interviews will be performed with therapists who have use the personalized outcomes forecast with at least one patient, to obtain reasons for (not) using the forecasts. The purpose is to uncover ways to improve the uptake of personalized outcomes forecasts or other electronic decision support systems in this patient population. Semi-structured interviews will be conducted once at 6 months follow-up.Different samples will be recruited to answer the different research questions  and categorical variables will be reported as frequencies and percentages.Outcomes to evaluate the impact of implementation are maximal and functional walking distance (measured by standardized treadmill test), quality of life, and shared decision-making. Outcomes will be operationalized as the change from baseline to a six-month follow up. We will perform an intention to treat analysis with the data exported from the Quality system database, since this database includes data of all patients treated with SET, with or without use of the personalized outcomes forecasts. A per protocol analysis will be perform using the data exported from the personalized outcomes forecasts. To compare pre- and post-implementation, segmented regression analysis will be performed. Segmented regression analysis is a commonly used method in ITS designs that accounts for possible changes in level and trend as result of implementation of a certain intervention . Serial Shared decision-making will be measured using the OPTION-5 score. OPTION-5 scores will be analyzed using a paired t-test to demonstrate a statistical significant difference in the mean overall score between pre and post measurement. Data will be tested for normality using skewness and kurtosis . If the Outcomes to assess the process evaluation of implementation in terms of utilization efficacy, include dropout rates  and reasons to (not) use the personalized outcomes forecasts (assessed by semi-structured interviews). The pre- and post-implementation drop-out rate will be compared using segmented regression analyses, as described for impact evaluation. Qualitative data on reasons to (not) use the personalized outcomes forecasts gathered through semi-structured interviews will be described in the overall synthesis of the findings.Formal medical ethical approval by the Medical Research Ethics Committees United ‘MEC-U’ was not required for this study under Dutch law (reference number 2020–6250). All physical therapists affiliated with Chronic CareNet adhere to the data delivery procedures as this is a participation conditions of the network. In other words, all affiliated therapists agree with the necessary use of data when participating in the network and thus also for the purpose of this study. Patients who receive care via a Chronic CareNet therapist provide consent for the use of their clinical data for research and clinical purposes. This enables a number of critical functions within Chronic CareNet; for example: the storage of patient data and recall of treatment results through visuals in the website, the use of aggregated data for quality improvement and research analyses, and the semi-automated generation of standardized documentation . Informed consent of patients is collected digitally through the Chronic CareNet website with a digital signature. By signing this informed consent, patients agree to the use of their data for research purposes. Data will be handled confidentially and in accordance to the General Data Protection Regulation (AVG).Patients and therapists undertaking the shared decision-making observations or semi-structured interviews will be separately consented prior to participation in this part of the project. After formal agreement to participate, therapists receive written information, informed consent forms and self-addressed envelopes by post for both themselves and the patient. For the observations, information is provided to the patient by the therapist. Both therapist and patient will sign two consent forms. All forms will be sent in the self-addressed envelope to the coordinating investigator, who will sign the forms and return one for the patient and one for the therapist.This protocol describes an Interrupted Time Series (ITS) study examining the implementation of personalized outcomes forecasts (KomPas) for physical therapy treatment of patients with intermittent claudication in the Netherlands. This pragmatic study design and approach (lacking exclusion criteria) aims to overcome selection bias and improve generalizability of study findings . AdditioTwo limitations should be considered for this study. First, the use of the personalized outcomes forecasts is not mandatory for the physical therapists within the Chronic CareNet network. Therefore, challenges may arise when implementing this (or any) new approach that necessarily affects workflow. Therapists will have to implement this tool into their practice routine and invest time to do so, based on internal motivation. Time pressure is high within the physical therapy profession and additional administrative workload is a barrier for implementation . AlthougThis planned study aims to improve patient-centered care for patients with intermittent claudication through use of a novel decision support tool that generates personalized outcomes forecasts. The tool has been designed to elicit shared decision-making and aid in the personalization and optimization of treatment.S1 Checklist(DOC)Click here for additional data file.


Phylogenetic relatedness is one of the important factors in the community assembly process. Here, we aimed to understand the large-scale phylogenetic relationship between alien plant species at different stages of the invasion process and how these relationships change in response to the environmental filtering process at multiple spatial scales and different phylogenetic extents.We identified the alien species in three invasion stages, namely invasive, naturalized, and introduced, in China. The occurrence records of the species were used to quantify two abundance-based phylogenetic metrics [the net relatedness index (NRI) and the nearest taxon index (NTI)] from a highly resolved phylogenetic tree. The metrics were compared between the three categories of alien species. Generalized linear models were used to test the effect of climate on the phylogenetic pattern. All analyses were conducted at four spatial scales and for three major angiosperm families.We observed significantly higher NRI and NTI values at finer spatial scales, indicating the formation of more clustered assemblages of phylogenetically closely related species in response to the environmental filtering process. Positive NTI values for the invasive and naturalized aliens suggested that the presence of a close relative in the community may help the successful naturalization and invasion of the introduced alien species. In the two-dimensional phylogenetic space, the invasive species communities significantly differed from the naturalized and introduced species, indicating that established alien species need to be phylogenetically different to become invasive. Positive phylogenetic measures for the invasive aliens across the spatial scales suggested that the presence of invasive aliens could facilitate the establishment of other invasive species. Phylogenetic relatedness was more influenced by temperature than precipitation, especially at a finer spatial scale. With decreased temperature, the invasive species showed a more clustered assemblage, indicating conservatism of their phylogenetic niche. The phylogenetic pattern was different at the family level, although there was a consistent tendency across families to form more clustered assemblages.Overall, our study showed that the community assemblage became more clustered with the progression of the invasion process. The phylogenetic measures varied at spatial and taxonomic scales, thereby highlighting the importance of assessing phylogenetic patterns at different gradients of the community assembly process. PhylogeHowever, the introduction of an alien species may also occur in a community with existing alien species belonging to different stages of the invasion process, i.e., introduced, naturalized, and invasive. Biotic interactions  between the alien species at a small spatial scale and environmental factors  at a large spatial scale may influence the community assembly process . The majThis study addressed this knowledge gap by characterizing phylogenetic relationships between alien community members at different spatial and taxonomic scales. Ecological traits are often phylogenetically conserved , and theSecondly, among the three stages of the invasion process, the invasive species have been found to possess certain ecophysiological traits  that aid them in adapting to a range of environmental conditions . MoreoveThirdly, the observed phylogenetic pattern can vary depending on the taxonomic scope (whole flora or family-specific) and phylogenetic framework (based on phylogenetic trees or a non-phylogenetic approach) . As specWe tested these three hypotheses for the alien plant species present in China. The history of alien plant introduction into China goes back more than 2000 years, and many aliens have become naturalized and subsequently invasive . With inSpecifically, the objectives of this study were to determine: 1) the variation of phylogenetic relatedness of alien species across spatial scales (hypothesis 1), 2) whether the three groups of alien species  show similar phylogenetic patterns (hypothesis 2), and 3) how the phylogenetic relationships change depending on the taxonomic scale (whole flora and family-specific) of investigation (hypothesis 3). We addressed these objectives by relating phylogenetic patterns of alien species across spatial scale, invasion process, and taxonomic scope with climate as an environmental filter.22.1We created a comprehensive list of alien plant species in China from three nationwide checklists published until 2021, namely, naturalized alien plants of China , the chThe occurrence records (latitude and longitude) of species in China were extracted from the Global Biodiversity Information Facility  and digi2.2We used a ‘mega-tree’ approach to generate a highly resolved phylogenetic tree  in R. Th2.3The phylogenetic relatedness was tested from the net relatedness index (NRI) and the nearest taxon index (NTI). These indices were developed by  and havehttps://geospatial.tnc.org/; date of access: 22 February 2022), and the provincial map (level– 1) of the country was downloaded from the GADM version 4.0.4 . We identified the species’ distribution across the different spatial scales using a custom script in R , Köppen-Geiger climate classes , geographic provinces , and ecoregions   on variations in phylogenetic measures of six community types  was first checked by using logistic regression models (the glm function in R).Based on the lower AICc (the AIC score corrected for sample sizes) values of the regression models . The meaFinally, Spearman’s rank correlation  was calculated to measure the strength and direction of the relationship between the phylogenetic relatedness of the six community types at each of the four spatial scales. All statistical analyses were conducted at species and family  levels. All statistical analyses were conducted in R; the details are provided in 3The 706 species  considered in this study belonged to the 397 genera and 94 families. The phylogenetic tree was highly resolved, with the species distributed among major angiosperm clades  of 1.38 ± 0.27] were found to be higher than NTI [-0.81 to 2.68 with an average (± se) of 1.05 ± 0.21)  and NTI  values  were significantly higher than that of the naturalized and introduced alien species  were mostly non-significant across the spatial scale  and ecoregion (ECOs) scales, respectively. These findings supported our first hypothesis, based on the concept that closely related species can respond more similarly to the environmental variation that is more noticeable at a finer spatial scale .The second hypothesis, i.e., the phylogenetic measures will vary between the alien species of three categories, with the invasive aliens showing the most clustered assemblage, was supported by multiple findings of this study. Firstly, the presence of introduced alien species in the community caused a clustered assemblage when the NRI values were considered (positive NRI) and an overdispersed assemblage when considering the NTI values (negative NTI). In contrast, positive NTI values were observed for the invasive and naturalized alien species. These findings indicate that although the existing lineages of the introduced species may lead to small mean pairwise distances, they do not always have a close relative present in the community. The positive NTI values for the invasive and naturalized species, on the other hand, resonates with the pre-adaptation hypothesis, which posits that a close relative in the community may help the successful naturalization and invasion of the introduced alien species . SecondlWe found few significant correlations between the phylogenetic relatedness metrics of the three species categories. The regression analysis also revealed the influence of community types and bioclimatic variables on the NRI and NTI values, more prominently at the ecoregion (ECOs) scale. Given that environmental filtering often drives phylogenetic clustering , these fThe phylogenetic pattern varied at the family level from that observed at the species level, thereby supporting our third hypothesis. Both the phylogenetic measures were positive for three alien species categories. With the decrease in the phylogenetic resolution, the species of the same family respond to the environmental gradients more similarly, which can explain the clustered assemblage within families. Indeed, compared to the species level, we observed more significant correlations between the NRI values of the three alien species categories at the family level. In each of the three families, the correlation analysis revealed that the NRI values of the three species categories were positively correlated mainly at finer environmental scales (ECOs). This pattern can be explained based on the similar response of all possible species pairs of the same family to the environmental filtering process . The shaHowever, the phylogenetic pattern was not always consistent across families. The invasive species of Asteraceae, either occurring alone or in combination with the other two alien species categories, showed a significantly stronger clustered community assemblage. This pattern became weaker and dependent on the spatial scale in Fabaceae, where significantly higher NRI and NTI values were only observed when the invasives cooccurred with the naturalized and introduced species. We observed no significant differences in the phylogenetic measures in Poaceae between the three species categories. The variations in phylogenetic patterns between families can be explained based on the families’ different evolutionary histories  and the Similarly, the influence of the environmental filtering process on phylogenetic relatedness was not consistent across the three families considered in this study. The effect of cold stress leading to increased phylogenetic clustering , as observed at the species level and for Fabaceae and Poaceae families, was not observed for Asteraceae invasive and naturalized species. In addition, the correlation analysis revealed a significant positive correlation of both phylogenetic measures between invasive and naturalized aliens of Asteraceae across all spatial scales. These findings indicate that the invasives and naturalized species of the family Asteraceae might have been subjected to the same environmental filtering pressure. This phylogeographic pattern was not observed in Fabaceae, where, for example, the NRI and NTI values of the invasive and naturalized species showed positive and negative relationships, respectively, with annual precipitation. The different growth forms of the Fabaceae aliens . Finally, our study also indicated that plant functional traits could influence phylogenetic patterns in response to the environmental filtering process; therefore, relating phylogenetic patterns with functional traits of alien plant species in future studies can provide novel insights into the invasion process. As the phylogenetic structure is often determined by interacting species present in each community, we suggest future phylogenetic analysis should consider the combination of native and alien species at multiple spatial and taxonomic scales to understand better the dynamics of recipient community changes across the invasion continuum.In conclusion, our study showed that the phylogenetic relatedness of the alien species varies across the invasion continuum. The pattern depends greatly on the environment and spatial scale of investigation. The invasive species community showed the most clustered assemblage, irrespective of the spatial scales. The influence of the environmental filtering process also varied between families, more so at finer spatial scales, although there was a consistent tendency for more clustered NRI for all three species groups. Overall, our study highlights the importance of assessing hierarchical phylogenetic patterns of alien plant species of different invasion stages across spatial and taxonomic scales. We have also identified specific scopes of improvements that can further advance our understanding of the phylogenetic changes across the invasion process. Firstly, the uneven number of species across different communities and taxonomic scales might influence the comparative assessment of the phylogenetic measures. However, using abundance-weighted phylogenetic measures addressed this problem to some extent. Secondly, the occurrence data used in this study to estimate the phylogenetic metrics were collected from GBIF and NSII, which often cannot adequately represent the actual distribution of the species in China . In addiThe original contributions presented in the study are included in the article/AB and YH conceived and planned the project. HF, XL, YL, JW, MY, and HP collected the data. AB, FT, HF, and NZ analyzed the data. AB, FT, NZ, and YH contributed to the interpretation of the results. AB wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.


Bandgaps of traditional phononic crystals (PCs) are determined using structural geometric parameters and material properties, and they are difficult to tune in practical applications. Piezoelectric PCs with lead zirconium titanate piezoelectric ceramics (abbreviated to piezoelectric PCs) have multi-physics coupling effects and their bandgaps can be tuned through external circuits to expand the application range of the PCs. First, the typical structures of piezoelectric PCs are summarized and analyzed. According to the structure, common tunable piezoelectric PCs can be roughly divided into three categories: PCs that only contain piezoelectric materials (single piezoelectric PCs), PCs composed of embedded piezoelectric materials in elastic materials (composite piezoelectric PCs), and PCs that are composed of an elastic base structure and attached piezoelectric patches (patch-type piezoelectric PCs). Second, the tuning methods of bandgaps for piezoelectric PCs are summarized and analyzed. Then, the calculation methods of the bandgaps of piezoelectric PCs are reviewed and analyzed. Finally, conclusions are drawn on the research status of piezoelectric PCs, shortcomings of the existing research are discussed, and future development directions are proposed. Phononic crystals (PCs) are periodic composite materials with lattice spacing comparable to the acoustic wavelength. They are of interest because of the profound effects of their periodic structure on wave propagation  and potential applications  . KushwahThe regulation of elastic waves in PCs is determined by their structural geometric parameters and material properties, which are often fixed and cannot be easily changed in practical applications. As a result, the practical application of PCs is greatly limited. However, the pre-existing state of stress in a PC, also known as the “prestress”, can have a strong influence on the propagation of waves in elastic structures. This effect provides a potential means to alter the characteristics of elastic waves by adjusting the prestress. Nevertheless, both experimental  and numePiezoelectric materials play a unique role in the research and design of tunable PCs and possess significant application value ,22,23. TThis study reviews the advances in the tunable bandgaps of piezoelectric PCs containing piezoelectric ceramics. The remainder of the paper is organized as follows. According to the structure, common tunable piezoelectric PCs can be roughly divided into three categories: PCs that only contain piezoelectric materials (single piezoelectric PCs), PC composed of embedded piezoelectric materials in elastic materials (composite piezoelectric PCs), and PCs that are composed of an elastic base structure and attached piezoelectric patches (patch-type piezoelectric PCs).Single piezoelectric PCs are a type of piezoelectric PC that utilizes a single homogeneous piezoelectric material. These PCs achieve their specific functionalities by varying the structural geometric parameters, such as thickness or cross-section size, and by incorporating periodic hole arrangements with embedded or attached periodic electrodes . The perC for the PZT periodically layered structure depicted in 2, 2. The 1D rod-type piezoelectric PC is not only simple in structure but also highly tunable in terms of bandgap. This makes it a valuable tool for designing new elastic wave devices and exploring novel elastic wave phenomena. One potential application is the design of spatio-temporal phononic crystals, which can be achieved by utilizing time-varying electrical boundary conditions. Additionally, these structures can be utilized to design electrically tunable elastic wave topologies, opening up further possibilities for controlling and manipulating elastic waves.Tuning the Bragg bandgaps through periodic electrical boundary conditions was first proposed by Degraeve et al. . They coTwo-dimensional piezoelectric PCs are mainly based on a piezoelectric pole or plate  whose suComposite piezoelectric PCs consist of piezoelectric materials embedded in elastic materials. The embedded piezoelectric materials include layers and columns. The study of layered structures mainly includes the effective properties of the piezoelectric multilayer and the influence of the cap layer. Kutsenko et al.  studied There is another composite piezoelectric PC where the piezoelectric material acts as a columnar scatterer. Oh et al.  found thIn summary, these two types of piezoelectric PCs generally use periodic electrodes to connect the piezoelectric material with external circuits. The bandgap is mainly generated via periodic electrical boundary conditions. With the increase in the dimensions of structures and the types of external circuits, the complexity and diversity of bandgaps are increasing. Studies on the coupling of piezoelectric PCs to complex external circuits are currently lacking. Some unique microstructures or related concepts such as resonance units have been introduced to promote an integrated design ,40,41,42Patch-type piezoelectric PCs are commonly made of piezoelectric materials and formed into piezoelectric patches applied by being affixed to the elastic body as sensors or actuators. Casadei et al.  combinedCompared with the piezoelectric PCs that use a single piezoelectric patch, the piezoelectric PCs using double piezoelectric patches are advantageous in tuning bandgaps. Piezoelectric parallel arrays are typical examples. They are powerful tools to change the equivalent mechanical impedance to control the dynamic fluctuation behavior by changing the tunable properties of parallel piezoelectric patches. Thorp et al.  controllIt is always challenging to control low-frequency elastic waves, especially with broadband attenuation. LR is expected to solve this problem. However, in previous studies, piezoelectric parallel arrays are usually sparsely mounted on the substrate, which is not conducive to generating LRGs with broadband and low-frequency characteristics. Chen et al.  proposedIn addition to those studies, researchers have focused on the binding of piezoelectric PCs to mechanical metamaterials to couple the mechanical and electromechanical LR and expand the bandgap. Chen et al.  considerIn conclusion, the number and spatial dimensions of piezoelectric plates in the unit of patch-type piezoelectric PCs can be structurally designed. Compared with the other two types of piezoelectric PCs, this type has a more diversified, complex, and mature structure and external circuitry. Patch-type piezoelectric PCs have more vibration and fluctuation patterns when the dimensionality of the structure increases. However, high-order vibration and wave modes will form the non-uniform electric field of such piezoelectric structures, which makes the common assumption of a uniform electric field no longer applicable. Therefore, theoretical research to solve this problem is urgently required. The combination of piezoelectric PCs and metamaterial provides a new method to obtain ultra-wide bandgaps. The application of external circuits and active control has also improved metamaterial bandgap characteristics.Piezoelectric materials have been used as physical components for passive and active control systems in piezoelectric PCs to control bandgaps. The passive control strategy has the advantages of low energy consumption, strong stability, and low cost. The performance of a passive control system is affected by its mechanical characteristics and external circuits. The external circuit determines the mode of power transmission and dissipation. Therefore, the design of piezoelectric parallel damping circuits will significantly affect the control effect of the structure ,75. ShunA semi-active circuit indicates that it can provide power for the system through the NC shunt circuit, and the NC shunt circuit can become unstable according to the component value. NC shunt circuits ,81 can lChanges in the external environment, temperature, and structural requirements significantly affect the regulation performance of the above shunt circuit ,89,90. APrevious studies used uniform circuits to shunt periodic piezoelectric patches. In contrast, some researchers have turned their attention to non-uniform external circuits. Wang et al.  set the In this subsection, the research status related to the active control of piezoelectric PCs is described. Wang et al.  proposedIn addition, digital synthetic impedance circuits are a new trend in active control. By combining a digital circuit with an NC circuit, Yi et al.  designedIn summary, through external circuitry or active control, unique elastic wave propagation modes can be triggered in piezoelectric PCs, which widen the Bragg scattering bandgaps, generate new LRGs, and fuse Bragg scattering and LRGs. External circuits and active control are moving toward a more diversified and integrated trend. The tuning of bandgaps for piezoelectric PCs is developing in the direction of more stability, flexibility, robustness, and efficiency.This section introduces bandgap calculations for piezoelectric PCs on two levels: the theoretical basis of the bandgap calculation model and the calculation method. The former mainly covers the piezoelectric plate or sheet theory, electric field distribution at the electrodes, and coupling relationship between the external circuit and the piezoelectric sheet. The latter mainly includes the transfer-matrix method (TMM), plane wave expansion method (PWEM), finite element method (FEM), and spectral element method (SEM).The analytical solution of the dispersion relation of the low-frequency symmetric Lamb wave of a piezoelectric plate with periodic strip electrodes can be obtained according to the piezoelectric plate theory and the assumption of a uniform distribution of the electric field between the upper and lower electrodes . The resCompared with single PCs, the research and analysis of patch-type piezoelectric PCs are more complicated because both piezoelectric or electromechanical coupling effects and the influence of external circuits on the elastic waves must be considered. To improve the efficiency of analysis and calculation, scholars have proposed simplified models for the theoretical or numerical calculation of the propagation characteristics of elastic waves. Among them, the most commonly used model is based on the assumption that the strain in the piezoelectric patch and electrical displacement on the electrode are equal everywhere . Take thBased on the above equivalent model and piezoelectric or electromechanical coupling effect model, the researchers propose more commonly used bandgap calculation methods: the TMM, PWEM, FEM, and SEM. The study of the PWEM was initiated by Wilm et al. , who appIn general, the basic model for bandgap calculation is based on the simplification of piezoelectric or electromechanical coupling effects and the equivalence of the effects on the circuit. For 2D piezoelectric PCs, the existing simplified theoretical models must be further studied and developed. No accurate simplified theoretical model has considered the influence of higher-order vibrations or waveforms on the structure of piezoelectric composite rods, beams, or plates. The development of the SEM can significantly simplify the research model of piezoelectric PCs, which provides convenience for related research.(1)Piezoelectric materials have outstanding advantages in controlling the elastic wave due to their electromechanical coupling characteristics and diversified external circuit control methods.(2)Single and composite piezoelectric PCs have three dimensions in space. The piezoelectric material is commonly connected to the external circuit through periodic electrodes. The bandgap is predominantly controlled by periodic electrical boundary conditions. When the dimensions and types of external circuits increase, the complexity of the bandgap calculation and the variety of bandgaps also increase.(3)Compared with the other two types of piezoelectric PCs, patch-type piezoelectric PCs have more diverse structural forms. The structural design can be conducted in terms of the number of piezoelectric patches and spatial dimensions in the unit. Patch-type piezoelectric PCs have more vibration and fluctuation patterns when the dimensionality of the structure increases. However, high-order vibration and wave modes in such piezoelectric structures can make the electric field inhomogeneous, so the uniform-electric-field assumption no longer holds. As a result, most theoretical and experimental studies on 2D patch-type piezoelectric PCs have primarily been limited to elastic patches and low or ultra-low frequency. The combination of piezoelectric PCs and mechanical superstructures provides a new method to achieve ultra-wide bandgaps. Using an external circuit or active control, a special elastic wave propagation mode can be induced to widen the bandgaps. In other words, new LRGs will be generated, and Bragg scattering can be combined with LR.(4)The development of FEM and SEM has promoted the visualization and simplification of bandgap tuning for piezoelectric PCs.Based on the analysis of a large amount of the literature, this study aims to classify and summarize the existing research on piezoelectric PCs and clarify their primary structure, regulation mechanism, and research methods. The main conclusions are drawn as follows.The following are future research directions concerning single and composite piezoelectric PCs. First, special microstructures such as resonant units or related concepts  should be explored further to promote the integrated design. Second, there is a lack of attention to the structural parameters and inherent shape of piezoelectric PCs; therefore, future studies should focus on optimizing the topology to improve the acoustic and vibration characteristics. Third, the coupling of complex external circuits should be studied, which has been ignored in most previous studies. Fourth, the method to break the symmetry of the structure, e.g., by changing the electric field boundary conditions of the upper and lower electrodes, to achieve the LRG of the anti-symmetric Lamb wave mode should be improved in the future.The higher dimensionality of the structure in the patch-type piezoelectric PC enables it to have more vibrational and wave modes. However, high-order vibration and wave modes will make the electric field in such piezoelectric structures inhomogeneous, which makes the commonly used assumption of a uniform electric field no longer applicable and considerably limits its application and research. The widely used research model is based on the simplified decoupling of an elastic force field and an electric field, and its application scope requires further research and development. In particular, the precise simplified theoretical model that considers the effects of higher-order vibration or wave modes of the structure remains insufficient. Nonetheless, such models can simplify complex analyses and improve the computational efficiency. The combination of patch-type piezoelectric PCs and mechanical superstructures provides a new method to achieve an ultra-wide bandgap that deserves attention. The existing related research models are based on simplifying the decoupling of the elastic force field and electric field. For 2D structures, there is currently no accurate simplified theoretical model that considers the influence of the high-order vibration or wave modes of the structure. However, such models can simplify complex analyses and improve the computational efficiency.In addition, it is necessary to quickly and accurately develop equipment that can process mechanical signals to make full use of the positive/negative piezoelectric effects. External control circuits with better performance  must also be designed. Integrating machine learning, deep learning, neural network, and other artificial intelligence concepts into the control of external circuits is a promising research direction. Existing related research and corresponding experimental verification research are relatively scarce and urgently need enhancement. The rapid development of advanced 3D/4D printing technology and the new generations of vibration and wave testing equipment have provided opportunities for relevant experimental research.


Achnanthidium minutissimum yielded clearer results (24.1%) than the total species matrix (22.6%). Therefore, we suggest excluding this taxon from calculations of TI, SI, or other indices when it is determined as A. minutissimum complex, because A. minutissimum complex was most abundant in both types of reaches in our study and has a wide ecological amplitude, which reduces the indicative power of the diatom community in the evaluation of environmental conditions and ecological status.The structure of phytobenthic diatom communities was studied to reveal differences between natural and channelized river sections in Slovenia. As part of the national monitoring of surface waters, samples of phytobenthos were collected at 85 sites throughout the country according to standard protocols. At the same time, basic environmental parameters were also assessed. Trophic (TI) and saprobic (SI) indices were calculated based on diatoms and other algae, while diversity indices and gradient analyses were performed only for the diatom community. The results showed that channelized rivers harbor significantly more diverse benthic diatom communities than natural sections, mainly due to the significantly higher number of motile diatom taxa that are able to take advantage of more nutrient-rich and less-shaded river sections because of their high adaptability. Selected environmental parameters explained 34% of the variability in diatom community structure when taxa were classified into ecological types. The removal of  Hydromorphological alterations are among the worst anthropogenic pressures affecting European rivers and streams  and are Several studies have reported the degradation of biotic communities and lower species numbers in channelized river reaches compared to natural reaches for a variety of aquatic communities, such as fish  and bent2 concentrations.Straightened and constricted river channels have higher flow velocities, resulting in differences in species composition and their proportions in aquatic communities compared to intact sites . RheophiAnother consequence of the channelization of rivers is their reduced ability to deal with pollutants in the form of degradable organic matter and inorganic nutrients . ChannelAn assessment of the ecological status of the surface waterbodies in the member states of the European Union (EU) also includes an evaluation of hydromorphology . The biological quality elements (BQEs), which are considered to be the most sensitive to morphological alterations in rivers according to the WFD , are benThere is an approach that uses the functional characteristics of diatoms as an alternative to the taxonomic composition of diatoms for assessing the quality of aquatic ecosystems . The claThe motile (M) taxa group includes fast-moving species that are capable of efficient locomotion and are adapted to disturbances by rapid water flow, as well as to high nutrient levels. Their ability to move efficiently enables them to select the most suitable microhabitat . An apprThe purpose of this study was to investigate how river channelization affects the diversity and structure of the benthic diatom community and whether diatoms also respond to this type of morphological alteration. Phytobenthic diatoms could be used as an additional BQE to complement the benthic invertebrates and fish that are used to assess hydromorphological pressures and whose validity is sometimes limited when assessing anthropogenic pressures on rivers in the form of hydromorphological alterations. The aims of this study were to find out (a) which environmental parameters significantly shape the diatom community composition and (b) whether there are differences in diatom community structure between natural and regulated rivers. The following hypotheses were made: (a) diatom species richness and diversity are higher in natural than in regulated waterbodies; (b) the values of TI and SI are significantly higher in regulated compared to natural rivers due to their lower self-purification capacity; and (c) different ecological diatom types respond differently to river channelization, indicating the possibility of using benthic diatoms for the assessment of anthropogenic morphological river alterations.A total of 163 diatom taxa were identified in all 40 investigated rivers; most of them were at the species level, with some exceptions at the genus level. In natural river sections, 141 diatom taxa were identified in 65 samples (average 24.9), while in channelized river sections, 117 diatom taxa were identified in 20 samples, with an average number of 28.6 diatom taxa per sample .p = 0.024) higher proportion in regulated river sections. The difference in high-profile (HP) taxa between natural and regulated river sections was only marginally significant (p = 0.063), with a lower proportion in channelized river sections. There were also differences in the order of proportions of ecological diatom types between natural and regulated river sections; however, the low-profile type (LP) had the highest proportion in both groups. The second most common ecological type in the natural river sections was HP, while in regulated river sections, the M taxa had a higher proportion. The order of contribution to diatom diversity was also not the same for both river groups (p = 0.018) in regulated rivers. Although the LP taxa accounted for half of the valves found , the SDI of the LP diatom metacommunity was lowest in both river groups, with significantly lower values (p = 0.026) for natural sections.The proportions of ecological types of benthic diatoms differed between the natural and regulated river sections , especiar groups . Speciesp < 0.01) in environmental parameters between the two groups for (a) altitude, as the channelized river sections were found at lower altitudes (p = 0.002), mostly in lowlands; (b) proportion of gravel (p = 0.003), which was higher in the natural river sections; and (c) conductivity, which was higher in regulated river sections (p = 0.005), reflecting a higher proportion of agricultural land adjacent to the regulated sections and their lower self-purification capacity.There were also significant differences in environmental parameters between the natural and regulated river section groups , which cThe results of the direct gradient analyses provided a list of nine environmental parameters that significantly shaped the diatom community , with coThe vector indicating the LP taxa shows exactly the opposite gradient as the sum of the abundances of the other algae in the phytobenthos. The gradient of SI based on other algae and the average depth of the water are also in the opposite direction than the proportion of the LP taxa, but the correlation is somewhat less clear.The proportion of planktonic taxa increased with water depth. These species are introduced to the phytobenthos with sedimentation from the water column, which is more intense at greater depths and lower velocities, respectively.The proportion of motile taxa increased with the temperature and depth of the water. Deeper water generally also means lower current velocities over the substrate, providing better conditions for motile species. Furthermore, deeper water also reduces light intensity, reaching the phytobenthos at the bottom. Higher temperatures also mean higher metabolic rates, which are generally higher in motile species than in other types.p = 0.02) diversity (SDI) of the diatom community in samples from regulated river reaches compared to natural ones. The effect of disturbance events on the diversity of a given community depends on its frequency and intensity, as formulated in the intermediate disturbance hypothesis [The structure of the phytobenthic diatom community did not show lower diversity in regulated river reaches than in preserved natural river reaches . On the pothesis . It seemp = 0.005), while channel shading was higher in the natural river sections, as expected, due to frequent removal of woody riparian vegetation along the channelized sections. However, the higher amounts of available nutrients and light in the channelized river sections had a positive effect on the benthic diatom community, resulting in higher diversity compared to the natural sections.Most of the environmental parameters assessed differed significantly between natural and regulated river sections . Conductp = 0.018) and diversity (p = 0.029), as well as the proportion of M species (p = 0.024) in the diatom community of the regulated river sections , as well as a higher number of taxa (p = 0.018), in channelized sections, it raises the diversity of the total benthic diatom community in channelized sections above the diversity in natural sections.Based on our results, M diatoms can also be used to assess the ecological impact of hydromorphological pressures, as this ecological type is characteristic for channelized sections. Because this type has a significantly higher proportion  are temperature and average depth of the water. Temperature has been most frequently cited as a significant factor in shaping diatom community composition , and the Adriatic Sea basin, which covers approximately 3750 km2 [The territory of Slovenia is divided into two drainage basins: the Black Sea or Danube basin, which make up the largest part of the Slovenian territory , while igneous rocks are rare, covering 1.6% of the surface . The cliSampling of the phytobenthos was carried out in 2011–2014 as part of the national monitoring of surface water quality according to the WFD . In totaAccording to the Slovenian national methodology of ecological status assessment for rivers using the phytobenthos and macrophytes , samples2 concentration and saturation, conductivity, and pH using a multimeter .In accordance with the Slovenian national methodology for the assessment of the ecological status of rivers based on the phytobenthos and macrophytes , in addiThe water current velocities were estimated according to a 4-level scale , and the water depth was also estimated in four categories . The turbidity of the water was estimated on a 3-level scale . The shadiness of the channel was assessed (in %). The substrate categories, as well as their proportions of the cover (in %) of the bottom within the sampled reach, were assessed according to AQEM 2002  for each3) in order to clean them of cell contents and other organic matter, according to standard EN 14,407 and the instructions of the Slovenian national methodology of ecological status assessment for rivers using the phytobenthos and macrophytes [®, a medium with a high refractive index, for permanent slide preparation. Permanent slides were examined with a light microscope  at a magnification of 1000×. The identification and enumeration of diatoms was performed according to standard EN 14,407 and the Slovenian national methodology of ecological status assessment for rivers using the phytobenthos and macrophytes [Phytobenthos samples were treated with concentrated nitric acid  were considered in further analyses. CCA and RDA ordination diagrams (biplots) were created with statistically significant factors. In addition, the analysis was performed with the entire taxonomic dataset but without the dominant taxon Achnanthidium minutissimum (Kütz) Czarn. Such an approach has already been used by Szczepocka et al. [A. minutissimum to be a pioneer species indifferent to environmental factors. Urrea-Clos and Sabater [A. minutissimum occurs within the highest number of areas and thus has a very wide ecological amplitude. Szczepocka et al. [A. minutissimum complex includes several species, and the ecological preferences of some species have not been studied enough yet.The influence of the recorded parameters on the composition of the diatom community was tested with direct gradient analyses, which were performed with the program package CANOCO 5.0 . Prelimia et al. . Since ta et al.  consider Sabater  also repa et al.  also poit-test (MS Excel). Because diatom species of the planktonic ecological type were absent in many samples due to the natural characteristics of Slovenian rivers that are unfavorable to phytoplankton, some of the analyses were not performed specifically for the planktonic ecological type.Differences in characteristics between the natural and regulated river sections were tested using Student’s Although a higher diversity of the benthic diatom community was expected in the natural river sections, our results confirmed the opposite—there was significantly higher diversity in the channelized sections. Significantly higher conductivity and nutrient availability (trophic index), as well as higher light availability due to less shading in the channelized river sections, are factors that favor phytobenthos growth; all were more favorable in the channelized sections, enabling greater diversity of the diatom community. Motile diatoms appear to be the most responsive and best adapted to take advantage of such altered conditions, and they increase the diversity of the benthic diatom community above levels found in natural river reaches.Achnanthidium minutissimum before calculating any diatom-based index, when determined as an A. minutissimum complex, to increase the indicative value of the phytobenthic diatom community.This suggests that diatoms can be used to assess human alterations of rivers, which are currently evaluated (according to WFD) using the benthic invertebrate community and fish community structure. The fish community and metrics calculated based on it often appear to be less efficient because the distribution of fish populations is highly dependent on the longitudinal connectivity of the river, which is often disrupted by dams. We propose that the selected diatom taxa that showed significantly different preferences for natural or channelized river reaches  should aA. minutissimum, or when the matrix of ecological types was used. In addition, the set of significant parameters was different when taxa were replaced by ecological types (Temperature and average water depth significantly shaped the structure of the diatom community when the entire species matrix was used, excluding al types .


The blood-brain barrier (BBB) has traditionally posed a significant challenge to the efficacy of systemic therapy in managing intracranial metastasis. However, recent insights into the immune-brain interface and the development of immunotherapeutic agents have shown promise in preclinical and early-phase clinical trials. Researchers have investigated combining immunotherapy with SRS to enhance treatment outcomes in patients with brain metastasis. The combination approach aims to optimize long-term control and overall survival (OS) outcomes by leveraging the synergistic effects of both therapies. Initial findings have been encouraging in the management of various intracranial metastases, while further studies are required to determine the optimal order of administration, radiation doses, and fractionation regimens that have the potential for the best tumor response. Currently, several clinical trials are underway to assess the safety and efficacy of administering immunotherapeutic agents concurrently or consecutively with SRS. In this review, we conduct a comprehensive analysis of the advantages and drawbacks of integrating immunotherapy into conventional SRS protocols for the treatment of intracranial metastasis.Solid tumors metastasizing to the brain are a frequent occurrence with an estimated incidence of approximately 30% of all cases. The longstanding conventional standard of care comprises surgical resection and whole-brain radiotherapy (WBRT); however, this approach is associated with limited long-term survival and local control outcomes. Consequently, stereotactic radiosurgery (SRS) has emerged as a potential alternative approach. The primary aim of SRS has been to improve long-term control rates. Nevertheless, rare observations of abscopal or out-of-field effects have sparked interest in the potential to elicit antitumor immunity  Brain metastasis describes the dissemination of neoplastic cells from a primary malignancy to the brain tissue and is a common complication in adults with solid tumors , 2. The SRS has emerged as a popular choice among these modalities, primarily due to its superior efficacy and reduced toxicity compared to WBRT . WBRT trAnimal studies have recently shown the occurrence of the abscopal effect (AE), a phenomenon in which the combination of radiation and dendritic cell growth factor leads to a reduction in distant metastases and improved disease-free survival compared to radiation alone . This efRecent advances in immunotherapy have led to the re-evaluation of the potential impact of RT, particularly through the use of hypo-fractionated ablative irradiation . The mecA systematic literature search was performed in the PubMed database, limited to articles published in the English language through April 28, 2023. The search strategy employed different keywords related to immunotherapy for the treatment of intracranial melanoma (M), non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), and other relevant malignancies. The identified publications were subjected to a screening process, during which non-English articles, as well as publications that fell under the categories of reviews, editorials, commentaries, case reports, opinion letters, and viewpoints, were excluded.The eligibility criteria for inclusion in the qualitative synthesis were as follows: patient-centered studies with SRS as a treatment modality within three months of systemic therapy, and relatively unbiased reporting of one or more of the following outcomes: local tumor control, distant tumor control, overall survival, radiation-induced adverse events, or other toxicities. The selection of studies for qualitative synthesis was based on a rigorous evaluation of the study design, patient population, and quality of reporting  at the level of tumor cells, where it induces significant DNA damage leading to cell death, and (2) at the level of the TME, where it activates multiple signaling pathways, inducing a pro-inflammatory state within the TME, and potentially causing harm to the surrounding stromal and endothelial cells .The interaction between radiation and the host’s immune response to brain metastases is multifaceted and influenced by numerous factors. Brain metastases can escape immune detection through several mechanisms, including the secretion of cytokines that suppress immune activity, decreased expression of TAA and major histocompatibility complex (MHC) class I, and the recruitment of regulatory T cells (Tregs) to the TME . In the Radiation has been shown to augment the presentation of TAA by DCs to both CD4+ and CD8+ T cells, thereby reinforcing the ability of the immune system to recognize and target tumor cells . FurtherIn mouse models, single-fraction doses of 15 to 25 Gy have been demonstrated to elicit a CD8+ T-cell dependent immune response, leading to regression of the treated tumor. Depletion of CD8+ T cells has been associated with local tumor persistence, increased distant metastases, and decreased survival . CombiniRecent discoveries have challenged the conventional idea that the brain is an “immunologically privileged” site due to the BBB and the absence of lymphatic drainage. Radiolabeled antigens have been found to travel through the subarachnoid space to cervical and retropharyngeal lymph nodes , and denStudies have shown that radiation exposure can increase MHC class I expression on glioma cells, leading to the infiltration of CD4+ and CD8+ T cells, while systemic administration of anti-CTLA-4 antibodies has been found to enhance the effector T cell response and decrease the number of Tregs . CombiniThe AE is defined as the suppression of unirradiated distant tumors or metastases following RT to a target lesion. The underlying mechanism is thought to be immune-mediated, where RT activates the immune system by revealing tumor-specific antigens that are processed by dendritic cells to activate T cells in neighboring lymph nodes . ResearcThe human immune system plays a crucial role in defending against cancerous cells . Among tSRS is a highly effective method for treating tumors and achieving improved local tumor control (LTC). However, distant relapse remains a common issue after exclusive SRS due to the persistence of an immunosuppressive TME. To address this issue, the incorporation of immune evasion inhibitors alongside SRS may be beneficial, potentially enhancing the antitumor immune response and overall treatment outcomes.The fundamental impact of ionizing radiation on biological systems is mainly attributed to the damage it inflicts on DNA molecules. Radiation’s immune-stimulating effects have been extensively studied over the past two decades. Studies have shown that local RT can enhance the systemic immune response by releasing TAAs from necrotic and apoptotic tumor cell debris. These antigens are then presented to CD8+ cytotoxic T cells by DCs, initiating an immune response that attacks tumor cells in other parts of the body where the antigens are recognized . PreclinThe optimal timing and dosage of radiation to maximize antitumoral immune stimulation have been elucidated through several research studies. For instance, Schaue et al. conducted a study on a mouse M model to examine the effects of total dose, dose per fraction, and number of fractions of RT on the RT-induced immune response and the outcomes . Tumor gThe parallel between the sequence of SRS and ICIs and the potential benefits observed with neoadjuvant, concurrent, and adjuvant ICI utilization offers a valuable perspective for optimizing the administration of SRS and ICIs in the context of brain metastases . The timAdministering ICIs prior to SRS holds promise in priming the immune system and enhance its response to SRS, resulting in improved LTC while inducing systemic antitumor effects . NotablyThe determination of the optimal sequencing and timing of SRS and ICIs remains an active area of investigation through ongoing research and clinical trials. The effectiveness and safety of these combined treatment approaches may vary based on factors such as tumor type, patient characteristics, and treatment regimens . As the Ionizing radiation is known to cause DNA damage and subsequent cell death and its impact on the immune system has been extensively studied in recent years . Local RFrom a clinical perspective, the application of SRS and ICIs for the treatment of brain metastasis has garnered significant interest, driven by preclinical and theoretical evidence. A number of studies have examined the optimal treatment sequence, SRS fractionation regimen and dosing, appropriate selection of ICIs, therapeutic efficacy, and potential adverse effects, generating a debate among experts in the field. The complexities surrounding optimal treatment strategies for brain metastasis are further compounded by the reliance on retrospective cohort analyses with small sample sizes, despite reporting improved LTC and OS rates with acceptable toxicity profiles. Notably, these studies primarily involve patients with M and the utilization of ipilimumab as the most frequently administered ICI. To address the current challenges, we present a comprehensive overview of studies examining brain metastasis in various cancer types, including NSCLC –52, M 5, 89, 90,The definition of concomitant administration of ICI and SRS exhibits significant variability among studies. A notable portion of the literature defines concomitance as the simultaneous delivery of SRS and ICI within a timeframe of four weeks before or after the initiation of ICI , 84, 91.Numerous studies have conducted comparisons between exclusive SRS monotherapy and combined ICI-SRS treatment with the overall consensus indicating improved LTC rates and patient outcomes with the concomitant administration of SRS and ICI , 93. MorFurthermore, a trend towards improved patient outcomes and LTC rates was observed in the patients who received concomitant SRS-ICI treatment, compared to those who received sequential treatment with no discernible difference in toxicity . The impTo provide a more comprehensive evaluation of the efficacy and safety of the combination of SRS and ICIs for brain metastasis, meta-analyses are warranted, given the limited patient population and the diversity of SRS and ICI treatment regimens across studies . One sucWhile previous studies have yielded valuable insights into the combination of SRS and ICIs, it is imperative to recognize that their conclusions are based on retrospective observational studies, which may not fully reflect the extent of their effects. The true therapeutic value of this modality can only be established through well-designed prospective clinical trials, which aim to minimize biases and confounding variables that may influence the results of retrospective observational studies. Therefore, it is crucial to await the results of these trials to gain a more robust understanding of the impact of combining SRS and ICIs on patient outcomes and to provide healthcare professionals with a clear guidance to make informed treatment decisions.Achieving the optimal dose and fractionation of radiation in SRS for treating spontaneous brain metastases poses a complex clinical challenge due to the need to balance effective tumor cell cytotoxicity against suppression of radiosensitive lymphocyte . AdvanceThe appropriate timing for administering immunotherapy in conjunction with RT remains a topic of ongoing research. Administering immunotherapy prior to SRS could enhance the antitumor response by allowing APCs and effector cells to be present when tumor cells are destroyed. However, this sequence could result in a reduced response if the circulating lymphocytes are recruited and then damaged by subsequent radiation. On the other hand, administering RT prior to immunotherapy could enhance expression of TAAs and increase BBB permeability, potentially improving drug delivery and immune cell infiltration. The optimal sequence of immunotherapy and RT depends on various factors, including radiation delivery parameters, the mode of action of immunotherapy, tumor histology, and overall mutational profile .It is widely accepted that ICI therapy should be administered either in conjunction with or prior to SRS or RT. A preclinical study of colorectal cancer treatment with a combination of 2 Gy x 5 fractions of radiation and a PD-L1 inhibitor has demonstrated that simultaneous administration of the inhibitor on either the first or fifth day is the most efficacious approach. However, administering the inhibitor seven days after radiation completion failed to improve survival compared to RT alone . The optIn a series of experiments evaluating the effect of the timing of administration of anti-CTLA-4 and anti-OX40 antibodies in relation to a single dose of 20 Gy radiation, the optimal timing of anti-CTLA-4 administration in relation to RT was found to depend on the dose and timing of the antibody . AdminisThe order in which anti-CTLA-4 antibodies are administered has a significant effect on treatment efficacy. Prior studies have indicated that administering the drug either two days before or concurrent with radiation completion leads to improved treatment outcomes compared to administration two days after radiation . AdminisRecent evidence highlights a paradigm shift in our knowledge of the BBB and its role in brain metastases treatment. While traditionally considered a protective barrier against immune cells, emerging data suggests that certain immune cells and treatments can penetrate the BBB, opening new avenues for therapeutic interventions. As a result, the combination of SRS and immunotherapy has gained significant interest as a potential synergistic approach to combat brain tumors.Radiation has been found to enhance the immune response, and T-cell-mediated responses are crucial in controlling tumors post-radiation locally and systemically. The potential benefit of combining of SRS and ICIs are promising, including improved OS, reduced local failure rates, and decreased risk of local recurrence, surpassing the outcomes of either treatment as a monotherapy. However, it is essential to acknowledge that existing data on this combination primarily stems from single-center retrospective cohort studies, warranting further investigation.The optimal administration sequence of immunotherapy with SRS remains uncertain and may vary depending on the specific systemic immunotherapy agent utilized. As we delve deeper into intricacies of this treatment combination, the possibility of increased incidence of severe adverse events compared to monotherapies still requires definitive determination.In light of these advancements, we need to consider whether SRS might lose its necessity in the treatment of brain metastases due to the efficacy of immunotherapy. This question challenges us to identify predictive factors that enable better patient selection for initial immunotherapy, while reserving SRS for cases of intracranial progression. Recognizing the importance of patient selection, we must develop strategies to tailor treatment plans for individual cases, optimizing therapeutic outcomes and reducing treatment-related toxicities. For instance, recent findings supporting the efficacy of immunotherapy in treating brain metastases underscores its clinical relevance . NonetheIn conclusion, the synergistic integration of SRS and immunotherapy holds immense potential in revolutionizing brain metastases treatment. To fully harness the potential of this combination, there is an imperative need to conduct additional well-designed prospective studies that elucidate the intricate interplay between SRS and ICIs. These studies hold the key to establishing robust clinical guidelines and tailored treatment plans, optimizing therapeutic outcomes for patients while mitigating the risk of treatment-related toxicities.As we pursue advancement in this dynamic field, we aspire to propel the frontiers of neuro-oncology in patients facing the challenges of brain metastases.DP and KY have made a substantial contribution to the concept and design of the article. KY drafted the article. SC and DP revised it critically for important intellectual content. ML approved the version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


The refinement of omics methods over recent years has enabled significant advances in microbiology. The functioning of the environment is extremely diverse, complex, and challenging to decipher, and consequently requires advanced molecular tools to address key scientific questions that remain poorly documented. Environmental omics aim at a better understanding of the metabolic processes of a wide range of organisms and/or complex microbial communities to improve phenotype-genotype linkages, thus providing novel insights into the key molecular players in response to environmental changes and invaluable information on microbial communities. In this context, this Research Topic showcases the power of environmental omics to characterize novel catalysts for biotechnological applications. The range of applications is large and includes the bioremediation of pollutants, design of innovative biosensors, screening for novel catalysts and therapeutic drugs, and bioproduction of novel chemicals and materials. We have encouraged scientists using omics to study different aspects of environmental processes to contribute to this Research Topic. The knowledge generated with these studies could be complemented by others with the ultimate goal of properly characterizing processes to develop knowledge-based biotechnological applications.Abdelmoneim et al. proposed in this Research Topic to replace the classical 16S RNA gene amplicon analysis with a taxon-specific qPCR for increasing the throughput of soil surveys which could also be used as a diagnostic tool for soil health. This study is an excellent illustration of how omics will become valuable diagnostic tools over the next decade, as recently envisioned . In this way, previously unknown functions could be discovered and annotated. However, improving methodologies and reducing their costs are of utmost importance for their widespread use. In this regard, Nitrospira has enabled the development of nitrogen removal strategies in wastewater treatment plants  into an efficient industrial process. Approaches such as design-build-test-learn cycles are well suited for this purpose (Dvorák et al., The works presented in this Research Topic illustrate different facets of the great utility of omics approaches for the rational development of a large variety of biotechnological applications. That the continuous progress in these methodologies are becoming more affordable will allow us to explore and understand new environments and processes to develop and optimize novel biotechnological applications.AO-A conceptualized and drafted the editorial. RM-E, JA, and SM-S provided critical review and insight to improve the writing. All authors approved the final paper.


This paper presents a comparative performance study of single-stage desalination processes with major configurations of membrane distillation (MD) modules. MD modules covered in this study are (a) direct contact MD (DCMD), (b) vacuum MD (VMD), (c) sweeping gas MD (SGMD), and (d) air gap MD (AGMD). MD-based desalination processes are simulated with rigorous theoretical MD models supported by molecular thermodynamic property models for the accurate calculation of performance metrics. The performance metrics considered in MD systems are permeate flux and energy efficiency, i.e., gained output ratio (GOR). A general criterion is established to determine the critical length of these four MDs (at fixed width) for the feasible operation of desalination in a wide range of feed salinities. The length of DCMD and VMD is restricted by the feed salinity and permeate flux, respectively, while relatively large AGMD and SGMD are allowed. The sensitivity of GOR flux with respect to permeate conditions is investigated for different MD configurations. AGMD outperforms other configurations in terms of energy efficiency, while VMD reveals the highest permeate production. With larger MD modules, utilization of thermal energy supplied by the hot feed for evaporation is in the order of VMD > AGMD > SGMD > DCMD. Simulation results highlight that energy efficiency of the overall desalination process relies on the efficient recovery of spent for evaporation, suggesting potential improvement in energy efficiency for VMD-based desalination. Water scarcity is a pressing issue that poses an urgent challenge to the world. Meanwhile, water quality problems are also increasing water-related health risks . ApproxiThere have been various reports that systematically investigated the membrane flux and energy efficiency of different MD configurations ,17,18,19Rigorous modeling of the MD configurations aids design, development, and optimization of MD desalination processes. Summers et al. established detailed analytical models for different MD configurations based on heat and mass transfer through the membrane and conservation equations in the flow channels . The modAccounting for the nonideal behavior of the aqueous electrolyte solution in MD modeling research is important for improving the accuracy and fidelity of the simulation results. Currently, some desalination studies treat saline solutions as ideal solutions , which sIn this study, the governing equations of DCMD, VMD, SGMD, and AGMD are formulated rigorously in Aspen Custom Modeler (ACM) V10.0 , together with the electrolyte NRTL model to provide thermophysical and transport properties. The MD models are validated and exported to Aspen Plus V10.0 for the system-scale process modeling investigation. A comparative analysis of different MD configurations is presented through a general criterion, defined as a function of saturation temperatures. The GOR–flux performance curve of MDs is obtained and the sensitivity of performance metrics with respect to operating conditions is evaluated for each MD configuration. The implications are provided as intrinsic guidelines for the design and operation of the MD desalination process.For the determination of comparative performance and energy efficiency of the different MD modules, detailed modeling of mass and energy transport involved in each configuration is critical. One-dimensional, steady-state models for various MD configurations with flat sheet geometry are developed from the mass, momentum, and energy balances in the MD channels, displayed in This section briefly summarizes the details of mass transfer involved in MD processes ,7,8. TheThe mode of mass transport through the membrane is primarily controlled by diffusion: Knudsen and molecular diffusion. Diffusion of vapor molecules experiences resistance from the collision with pore wall and stagnant molecules, i.e., air trapped inside pores. The vapor molecule–pore wall collision is analogous to free molecular diffusion. In free molecular diffusion, molecules of low-density vapor travel through the pore without colliding with other molecules but the pore wall; hence, the free molecular diffusion is described by Knudsen diffusion. In the molecular diffusion process, vapor molecules collide with air molecules; hence, the binary diffusion of vapor–air is best described using the molecular diffusion process. The Knudsen and molecular diffusion are expressed in Equations (1) and (2), respectively.Here In general, the Antoine equation is used to estimate the vapor pressure of water at saturation, pw* . SelectiApart from  with Kn ,37.(4)JFor the case of VMD , there eurations .(5)Jw VIn the following, we first elaborate on details of transport on the feed side for all the configurations as feed side equivalent for all the selected configurations. We then discuss the details of the model for the permeate side in each configuration.The common feature in all four MD configurations is the feed channel. The hot feed stream supplies the heat of vaporization and accompanying heat loss through the membrane, and the heat transfer by convection is due to the temperature gradient across the boundary layer adjacent to the membrane surface. The hydrophobic membrane theoretically offers 100% rejection for dissolved solids. Therefore, electrolyte concentration builds up on the surface of the membrane, which leads to a concentration gradient across the boundary layer, also known as concentration polarization. The transport in the feed channel is described using a set of mass, momentum, and energy balance equations (Equations (7)–(10)) over the control volume, as depicted in The heat transfer through the boundary layer (e and Pr .(11)qf=The permeate side of the DCMD module is very similar to that of the feed side. Pure water flowing through the permeate channel provides a condensing surface for the permeating vapor. The distillate stream receives heat from the condensing vapor, as well as the heat conducted through the membrane, and the heat transport is defined as:The condensing vapor is in equilibrium with pure water at the membrane surface temperature on the permeate side  flows through the permeate channel to reduce the water partial pressure. The partial pressure of water on the permeate–membrane interface (membrane .(16)pw,The water evaporated at the feed–membrane interface enters the permeate channel and remains in the vapor phase. Therefore, the heat conducted through the membrane will exchange sensible heat with moist air. The heat flux through the boundary layer in the permeate channel is equivalent to the heat of conduction through the membrane.The exclusive feature of AGMD is that an air-filled chamber, generally known as an air gap, is in contact with a coolant channel. A condensing plate separates the air gap and coolant channel. Water vapor leaving the membrane eventually condenses on the plate. A thin film of condensate is then formed on the plate. Therefore, water vapor experiences an additional molecular diffusion in the air gap. The overall vapor flux is the result of diffusion flux through the membrane and molecular diffusion flux in the air gap ,40. Thusing film . HoweverThe thickness of the air gap (L × W) for feasible flux production in terms of saturation temperature. As reported in Equation (23) the overall vapor flux in MD processes can generally be expressed as the product of permeability  appears the lowest, and it strongly depends on the gap thickness, showing a decreasing trend as air gap thickness increases. Vapor permeability in the membrane  is much higher than that of the air gap (Cgap), regardless of the air gap thickness. Therefore, overall vapor permeability (Cov) in the AGMD process closely follows the permeability in the air gap (Cgap). Vapor transport in AGMD experiences resistance from Knudsen and molecular diffusion inside the porous membrane and molecular diffusion in the air gap. All mass transport resistance is effective in series. Since permeability is reciprocal of mass transport resistance, the vapor transport region with the lowest vapor permeability is the flux-controlling region. The permeabilities of vapor transport regions at varying gap thickness are plotted in Vapor permeability in the air gap, as evident from The differences in permeate side configuration of MD modules bring differences in their mass and heat transport modes. Even with the same membrane in every module, it is difficult to make a direct comparison of performances among the MD configurations. Nonetheless, MD modules can be compared qualitatively in terms of individual thermal efficiency, the extent of heat recovery, and energy consumption in desalination processes per unit of water recovered.In the MD module, part of the heat supplied by the hot feed through the boundary layer in the feed channel  distillate flow in DCMD, (b) permeate pressure in VMD, (c) airflow in SGMD, and (d) coolant temperature in AGMD. Desalination with AGMD offers the minimum STEC among all the MD modules as low as 79 kWh/m3. The high value of 3. The efficient recovery of heat from the permeate stream in an external heat exchanger overcomes the poor thermal efficiency of the DCMD module. The opposite is observed in SGMD and VMD. The SGMD module, with much higher thermal efficiency, consumes more energy than DCMD to produce desalinated water. Poor extraction of heat from the vapor–air mixture due to partial condensation of water vapor raises the eventual energy consumption. A VMD configuration with 100% thermal efficiency (The important features of each MD configuration are summarized qualitatively in This work presents a comparative study on the performance of four different MD modules for the desalination of hypersaline brine solution, with a special focus on identifying theoretical MD module sizes from the standpoint of mass transfer mechanisms. Calculations performed in this study are supported by rigorous simulation models of MD modules developed in ACM together with an appropriate thermodynamic model for thermophysical and transport property estimation to yield high-fidelity simulation of the MD-based desalination process. Furthermore, flowcharts of the desalination processes are established in Aspen Plus to ensure mass and energy balance closure. Simulated GOR flux in response to permeate conditions for sufficiently large modules can be transferable for the design of MD-based desalination processes on a pilot and industrial scale. The results highlight the importance of maximum extraction of spent heat from the permeate stream for the design of an energy-efficient and high-throughput desalination process with a VMD module.