The efficacy of intravenous (IV) vedolizumab vs subcutaneous (SC) adalimumab for the treatment of moderately to severely active ulcerative colitis (UC) was assessed in the VARSITY clinical trial, which demonstrated for the first time in a head-to-head clinical trial setting the superiority of IV vedolizumab with respect to clinical remission and endoscopic improvement. Both therapies offer better clinical outcomes compared with immunomodulators and corticosteroids but are often more expensive than other pharmacologic treatment options. Thus, payers and decision makers face the task of leveraging finite resources for optimal health benefits, which can be aided by the use of cost-effectiveness models.To assess the cost-effectiveness of IV vedolizumab vs SC adalimumab from a US payer perspective using head-to-head data from the VARSITY trial.A cohort decision tree was developed to estimate the costs and clinical outcomes associated with IV vedolizumab vs SC adalimumab to treat adults with moderately to severely active UC. Simulated cohorts began the model at treatment induction and continued to maintenance treatment with vedolizumab or adalimumab unless experiencing nonresponse or serious adverse drug reaction (ADR), in which case those patients transitioned to second-line treatment with tofacitinib, infliximab, or golimumab, where they could achieve response and/or remission or not. Those who still did not achieve response or remission or who had a serious ADR transitioned to a state of nonresponse for the remainder of the model or received surgery. The process was modeled for patients who were treatment naive and treatment experienced at baseline separately. Efficacy and safety inputs for vedolizumab and adalimumab were taken from the VARSITY trial, and corresponding inputs for other biologics were derived from a network meta-analysis. All clinical inputs were extrapolated over 2 years. Direct medical costs (expressed in 2019 US dollars) included those related to drug acquisition and administration, ADRs, routine monitoring, and additional treatment procedures. Outcomes were not discounted given the short time horizon. Univariate sensitivity and scenario analysis were applied to evaluate the robustness of the model to underlying parameter and structural uncertainty.Initial treatment with vedolizumab was associated with a higher remission rate at 2 years (73.5% vs 71.5%) and higher persistence (22.0% vs 14.4%) compared with adalimumab. Total direct medical costs were lower for the vedolizumab cohort , primarily driven by the lower annual drug acquisition cost of vedolizumab . When endoscopic improvement was used as the outcome measure, IV vedolizumab was also associated with higher endoscopic remission and lower overall costs.With better clinical outcomes and lower direct medical costs over a 2-year model horizon, vedolizumab IV was the dominant treatment strategy vs adalimumab SC in adults with moderately to severely active UC. Outcomes were driven primarily by the probability of major ADRs and induction response. What is already known about this subjectBiologic treatments for ulcerative colitis (UC) are associated with high drug costs but confer better clinical outcomes compared with immunomodulator therapy.Vedolizumab was associated with better clinical outcomes for patients with moderately to severely active UC vs adalimumab in the VARSITY head-to-head trial.The cost-effectiveness of vedolizumab vs adalimumab in UC has been demonstrated in the United Kingdom, Japan, and China, but no such analysis has recently been conducted in the United States.What this study addsVedolizumab was associated with better clinical outcomes and lower direct medical costs over a 2-year horizon compared with adalimumab for the treatment of moderately to severely active UC.The economic benefits of vedolizumab were driven primarily by lower drug costs for patients initiated on vedolizumab therapy.This is the first study from a US payer perspective to evaluate the cost-effectiveness of vedolizumab vs adalimumab in UC based on head-to-head data from the VARSITY trial.1 The prevalence of UC in the United States is 286 cases per 100,000 in the general population.2 In 2016, the lifetime US direct medical cost for patients with UC was estimated to be $377 billion.3 Other US-based estimates have found that the annual direct and indirect costs associated with UC are between $8.1 billion and $14.9 billion.4Ulcerative colitis (UC) is a form of inflammatory bowel disease characterized by chronic relapsing-remitting inflammation of the colon.5 Biologic UC treatments traditionally have high drug acquisition costs yet provide comparatively better clinical outcomes compared with immunomodulators.7 Therefore, to guide resource allocation toward cost-effective UC treatments, payers and other stakeholders must weigh the costs and clinical benefits of the available advanced treatment options.10 Vedolizumab has been found to be more cost-effective compared with immunosuppressive therapy in patients with moderately to severely active UC in the United States, United Kingdom, Japan, and China for anti-TNF-naive and anti-TNF-experienced patients.15The American Gastroenterological Association (AGA) and American College of Gastroenterology have recommended immunomodulators and biologic therapies for long-term management of moderately to severely active UC. This includes antitumor necrosis factor (TNF)-α therapies , anti-integrin therapy (vedolizumab), anti-interleukin-12/23 therapy (ustekinumab), and Janus kinase inhibitor therapy (tofacitinib).10 and it can be more flexible than other analyses because it allows for varying clinical and economic inputs to investigate alternative scenarios and assess the effect of uncertainty on modeled outcomes. However, many cost-effectiveness analyses are limited by a lack of head-to-head clinical trial evidence for the treatment strategies being assessed.Cost-effectiveness analysis is useful for guiding optimal allocation of finite resources,16This analysis assessed the cost-effectiveness of intravenous (IV) vedolizumab vs subcutaneous (SC) adalimumab from a commercial payer perspective in the United States and integrated the comparative efficacy inputs from the phase 3 VARSITY trial, the first head-to-head trial comparing 2 biologic therapies  in adults with moderately to severely active UC.17 Alternative scenarios assessed outcomes for anti-TNF-naive and anti-TNF-experienced populations independently.The modeled patient population consisted of adult patients with moderately to severely active UC (Mayo score 6-12 and endoscopic subscore ≥ 2) who had inadequate response, loss of response, or intolerance to 1 or more corticosteroid, immunosuppressive, and/or anti-TNF agent. Because previous treatment with an anti-TNF therapy can affect subsequent clinical outcomes, the model evaluated clinical outcomes separately for anti-TNF-experienced and anti-TNF-naive subgroups and then aggregated them for the overall population results. Base-case percentages of anti-TNF-naive and anti-TNF-experienced patients were 79% and 21%, respectively, consistent with the percentages in the VARSITY trial. The relative distribution of these subgroups was based on the distribution reported in the VARSITY clinical trial.18) was developed to compare vedolizumab IV and adalimumab SC. The model estimated direct medical costs  over the 52-week trial period and extrapolated the clinical outcomes for an additional 52 weeks  or to treatment with chronic immunosuppressants if the other advanced therapies were contraindicated. Patients could achieve response and remission on these downstream therapies. In this model, patients who continued to not respond or achieve remission either remained in a state of nonresponse or underwent curative surgery.Costs and clinical outcomes were not discounted because of the short time horizon of the model. Each branch of the decision-tree model was weighted by event probabilities and the direct costs associated with each treatment or outcome . The ana19The vedolizumab IV cohort received induction therapy of 300 mg at weeks 0, 2, and 6. Those who responded to vedolizumab IV induction began maintenance therapy of 300 mg every 8 weeks. The adalimumab SC cohort received induction therapy of 160 mg on day 1 and 80 mg on day 15. Those who responded to adalimumab SC began maintenance therapy of 40 mg every 2 weeks. Patients could continue maintenance therapy for the remainder of the model. Treatments given after the initial therapy failed were dosed according to the approved label for each respective product. Wholesale acquisition costs (WACs) were collected from IBM Micromedex RED BOOK.Patients with inadequate response to induction therapy were switched to a second-line treatment option  until lack of treatment response or until a serious ADR occurred. Patients who did not achieve response or remission on second-line treatment proceeded to a state of perpetual nonresponse for the remainder of the model, while accruing the average weekly cost of pharmacotherapies in the model, except for some patients (25% in the base case) who underwent curative surgery.17 Response to induction therapy was defined as a decrease from baseline in total Mayo score of 3 or more points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of 1 or more or absolute rectal bleeding subscore 1 or less. Remission following maintenance therapy was defined as a total Mayo score of 2 or less, with no subscore greater than 1 and a rectal bleeding subscore of 0. Endoscopic improvement was defined as a Mayo endoscopic subscore of 1 or less.Efficacy data were derived from a recent network metaanalysis .17 Respo20 A major ADR was defined as a serious infection requiring a visit to the emergency department or hospital admission for inpatient care. Upper respiratory tract infection was chosen to represent minor ADRs, consistent with previously published economic models.20The health care resource utilization (HCRU) components examined included outpatient visits, inpatient stays, emergency department visits, endoscopy, laboratory tests, drug administration by infusion, and treatment for ADRs and were estimated using data from a targeted literature search . ADRs weThe model included 1-way univariate sensitivity analyses in which relevant inputs of the model were varied, one at a time, from the mean to low and to high values. The outcomes of the sensitivity analyses at 2 years were compared with the base model, and inputs were ranked by their relative impact according to the magnitude of the difference in the incremental net monetary benefit. The magnitude of each impact was defined as the absolute value of the difference in incremental net monetary benefit when using the low value vs the high value. Herein, we report the 5 most influential inputs.17 All trials received approval by the Institutional Review Board, and all patients in these trials provided written informed consent. No additional consent or approval was considered necessary for the present study.Efficacy data were derived from a network meta-analysis of published clinical trials.A similar percentage of patients who initially started with vedolizumab IV and adalimumab SC achieved remission at 2 years . Of these, a higher percentage of patients who initially started on vedolizumab remained in remission on vedolizumab rather than with downstream treatments at the end of year 2 (22.0%) compared with 14.4% of patients who initiated on adalimumab.Total direct medical costs over 2 years in the vedolizumab arm were $100,022 per patient compared with $151,133 in the adalimumab arm . The difAdministration costs for the adalimumab cohort were primarily from downstream IV-infused treatments. Routine monitoring costs were similar ($181 for both cohorts). Direct costs associated with other HCRU were lower with vedolizumab than with adalimumab  because of the higher failure rates of adalimumab. Vedolizumab was also associated with greater endoscopic improvement than adalimumab .A similar percentage of anti-TNF-naive patients initially treated with vedolizumab or adalimumab achieved remission at 2 years , but total costs over 2 years per patient in the vedolizumab arm were estimated to be $90,129 compared with $106,757 in the adalimumab arm .Results of the 1-way univariate sensitivity analysis of the base case at 2 years indicated that the most influential variables were the probability of major ADRs during the induction phase associated with vedolizumab IV or adalimumab SC . The nexThis cohort decision-tree model incorporated data from a head-to-head study of vedolizumab and adalimumab in patients with UC and thus may provide more reliable outputs than models using indirect comparisons. The model demonstrated that vedolizumab IV dominates adalimumab SC by providing greater clinical efficacy, as well as lower overall costs in adults with moderately to severely active UC. Costs were lower with vedolizumab IV for both anti-TNF-naive and anti-TNF-experienced patients. The difference between treatment groups was driven by drug costs, offsetting the higher administration costs associated with IV vs SC delivery. Treatment decisions should be centered on the patient’s goals and made within a cross-functional health care team. When multiple treatment options are appropriate, choosing the most cost-effective treatment can help address rising health care costs in the United States.16 Difficulties in comparing cross-trial remission rates between vedolizumab and adalimumab have been highlighted previously,16 but the network meta-analysis evidence used herein to account for the impact of subsequent therapies on patients who did not initially achieve remission with vedolizumab or adalimumab is consistent with the head-to-head clinical trial data.According to this model, the difference in the proportions of patients who achieved remission while remaining on their initial treatments over a 2-year period was consistent with the 8.8% difference observed in the head-to-head VARSITY trial over 52 weeks.21 An earlier US study indicated that cost per endoscopic improvement event was approximately 5% lower with vedolizumab than with adalimumab, with drug cost being the main cost driver over a 1-year time horizon.12 Here, vedolizumab was associated with greater endoscopic improvement and lower overall costs, which is consistent with a lower cost per endoscopic improvement.We evaluated the model by comparing it to the results of other similar publicly available research. Pharmacoeconomic outcomes were consistent with other studies investigating the cost-effectiveness of vedolizumab vs adalimumab.13 Likewise, vedolizumab was cost-effective in the United Kingdom vs adalimumab , having been associated with more QALYs and longer time spent in response and remission states.21 Jansen et al reported that costs per patient in sustained remission in anti-TNF-naive and anti-TNF-experienced patients were £95,833 and £116,100, respectively, for vedolizumab and £148,087 and £217,457 for adalimumab.14 Vedolizumab also was dominant over the anti-TNFs infliximab and golimumab in these UK analyses.21 Similar outcomes were also seen in anti-TNF-naive and anti-TNF-experienced patients.11In Japan, vedolizumab was associated with higher drug-related costs over the lifetime of an anti-TNF-naive patient than was adalimumab , but vedolizumab was cost-effective due to the greater amount of time spent on treatment, in response and remission, and because fewer surgeries were required compared with adalimumab.22 These results were due to a relative cost per vedolizumab dose that was approximately 7 times higher than that of adalimumab,22 whereas in the our US analysis, weekly costs were closer for induction treatment with these 2 drugs and less expensive for maintenance treatment with vedolizumab.In contrast, a Spanish cost-effectiveness study by Trigo-Vicente et al reported that over a 10-year period adalimumab was cost-effective compared with vedolizumab and other anti-TNFs.18 The use of published drug prices may be considered a strength due to transparency and consistency of reporting across. Individual payers may consider how their specific rebates/discounts affect the conclusions.The inclusion of clinical inputs from the VARSITY head-to-head trial is an important strength of this research. The VARSITY trial allowed for stronger clinical and safety comparisons. Adaptation from the Milev model is a strength of this research because it allows for further validation of previous conceptual models with the inclusion of stronger comparative research.20 upper respiratory tract infections (and their associated cost) are not necessarily representative of all minor ADRs associated with vedolizumab or adalimumab SC treatment. However, the safety profile of treatments is dependent on their mechanism of action, making comparisons of safety outcomes beyond common ADRs difficult.Data on loss of efficacy and discontinuation over time are incomplete; however, it is not expected that differences between treatments would have been sufficiently large to substantially affect these results. Likewise, costs relating to minor ADRs were limited to upper respiratory tract infections as a representative minor ADR. While common, and used as a representative minor ADR in other pharmacoeconomic models of UC,18 Outcomes from the randomized controlled trial used as inputs in this analysis may also not be fully reflective of the costs incurred and outcomes observed in a real-world setting.Only the costs for branded products that were compared in the head-to-head VARSITY study were used in our analysis instead of the full constellation of treatments used in patients with UC, for which there are currently no head-to-head comparisons. Likewise, subsequent treatments were restricted to those selected by Milev et al to facilitate a contemporary comparison of this updated model, which incorporated new data.Using only branded biologics for costs may limit the generalizability, given that biosimilars are commonly used. Furthermore, WACs used to estimate drug acquisition costs do not reflect the real-world discounts and rebates that result in a net price of the medications so are not reflected in the cost-effectiveness results. WAC is a transparent and publicly available price, which avoids having to make an assumption about a single discount rate that is applied broadly. This transparency and consistency will allow any reader to modify the outcomes reported here based on their own private discounts. Discounts or rebates that significantly lower the cost of adalimumab in comparison with vedolizumab could result in vedolizumab no longer being dominant.5It should also be noted that the AGA guidelines make a conditional recommendation with a low level of evidence to use ustekinumab or tofacitinib instead of adalimumab or vedolizumab, for inducing remission in patients with UC previously treated with infliximab, particularly in those with primary nonresponse.This US-based, commercial payercentric economic model demonstrated that vedolizumab treatment was associated with greater clinical efficacy and lower total costs over a 2-year period in adults with moderately to severely active UC in comparison with adalimumab. Thus, initiating treatment with vedolizumab rather than with adalimumab may provide a clinical benefit to patients, while also providing cost savings for health care organizations.


The SARS-CoV-2 pandemic has underscored the need for field specimen collection and transport to diagnostic and public health laboratories. Self-collected nasal swabs transported without dependency on a cold chain have the potential to remove critical barriers to testing, expand testing capacity, and reduce opportunities for exposure of health professionals in the context of a pandemic.We compared nasal swab collection by study participants from themselves and their children at home to collection by trained research staff.Each adult participant collected 1 nasal swab, sampling both nares with the single swab, after which they collected 1 nasal swab from 1 child. After all the participant samples were collected for the household, the research staff member collected a separate single duplicate sample from each individual. Immediately after the sample collection, the adult participants completed a questionnaire about the acceptability of the sampling procedures. Swabs were placed in temperature-stable preservative and respiratory viruses were detected by shotgun RNA sequencing, enabling viral genome analysis.In total, 21 households participated in the study, each with 1 adult and 1 child, yielding 42 individuals with paired samples. Study participants reported that self-collection was acceptable. Agreement between identified respiratory viruses in both swabs by RNA sequencing demonstrated that adequate collection technique was achieved by brief instructions.Our results support the feasibility of a scalable and convenient means for the identification of respiratory viruses and implementation in pandemic preparedness for novel respiratory pathogens. Challenges to global control of SARS-CoV-2 have underscored the need for accurate, safe, and rapidly scalable laboratory testing to inform rapid diagnosis and implementation of appropriate clinical and public health measures. Furthermore, early detection of emerging infectious disease threats is critical to limit spread. Over the last 4 decades, 1-3 newly emerging pathogens have been identified annually . Due to Lower per-sample sequencing costs, accessible results through user-friendly analysis tools, and rapid turnaround of sequencing data have led to a growing number of diagnostic and public health laboratories applying NGS-based pathogen detection and profiling, which has enhanced and accelerated the detection and surveillance of emerging viruses -9. ReliaHowever, community- and household-based sampling strategies offer potential advantages over sampling by health care workers in preparation for and during an outbreak. Specifically, anterior nasal swabs represent a noninvasive means for the detection and profiling of respiratory viruses via molecular diagnostic methods, provided appropriate measures to maintain sample integrity are taken -14. FurtIn this feasibility study, we assessed detection of respiratory viruses by shotgun RNA sequencing using a room temperature–stable at-home nasal swab sampling kit, comparing swabs collected by participants to swabs collected by trained research staff. We also determined the acceptability to participants of collecting nasal swabs from their children and potential barriers to collection at home.The inclusion criteria were families with children younger than 7 years who lived in Salt Lake County (to facilitate the required home visits) and in which the parent was able to read English. Invitation letters were sent to 34 families that were currently part of an ongoing cohort study (the Utah Children’s Project). In addition, a request for volunteers was posted on the Utah Children’s Project Facebook page. In total, 32 families responded, of which 4 declined to participate, 4 were not eligible, and 3 were eligible but not able to schedule a visit in the time window of the study. Thus, 21 families were enrolled over a period of 7 weeks from February to April 2018. This number of families was based on logistical considerations, without any power calculations. Study surveys were collected by paper questionnaire during the scheduled home visit to collect participants’ age, gender, ethnicity, race, household composition, and feedback on the sample collection process. The questionnaire was not pilot-tested or otherwise validated.).All aspects of this study were approved and carried out in accordance with the University of Utah Institutional Review Board  were used for collection of nasal swab samples. The research staff member also provided a link to an existing video demonstrating collection procedures and access to an iPad (Apple) to view the video immediately prior to sample collection. Participants were given the opportunity and time to independently review the instructions, collect the nasal swab samples, and package them for mailing. Adult parents collected their own sample and separately collected the sample for their child. During this time, research staff were present but did not aid or guide in self-collection. Each participant collected 1 nasal swab and sampled both nares with the single swab. Once all the participant samples were collected for the household, the research staff member collected a separate single duplicate sample from each individual, again sampling both nares. Samples collected by research staff were transported at ambient temperature and transferred to a –80 °C freezer on the same day. Samples were labeled with IDs corresponding to the following information: family ID (F01-F21), participant type , and collection type .At the beginning of the home study visit, adult participants completed a pen and paper enrollment questionnaire about demographics and household characteristics. Questions were taken from the National Children’s Study enrollment questionnaire . At the RNA was extracted using the ZymoBIOMICS DNA/RNA Miniprep kit (Zymo Research). cDNA libraries were prepared using the Trio RNA-Seq kit (NuGEN Technologies), quantified by quantitative-PCR using the KAPA library quantification kit (Roche), and sequenced on a NextSeq500 instrument (Illumina) to a depth of approximately 15 million 150-base-pair reads per sample. Sequencing data were demultiplexed allowing for no mismatches in the barcode sequences. Adapter sequences were trimmed, and the data were quality-filtered. Respiratory viruses were detected and viral genome sequences were assembled using the Explify Platform . For phylogenetic analyses, complete human metapneumovirus (HMPV) genome sequences were obtained from GenBank. Multiple sequence alignments were performed with Geneious, and neighbor-joining trees were constructed with the Tamura-Nei method and bootstrapped using 500 replicates (Geneious v11.1.5).Proportions and 95% CIs were calculated. Agreement between self-collected and staff-collected samples was assessed by Cohen κ statistic, which was estimated using Prism version 8.3.0 (GraphPad).). Most adult participants  indicated they had a bachelor’s degree or higher. Of the 21 families, 10 (47.6%) reported a recent upper respiratory illness, but the exact time frame was not defined.The demographics of the study participants are presented in Most adult participants  collected nasal swab samples with no  or little  self-reported difficulty . All enrA median of 9.05 (IQR 8.21-10.2) million sequencing reads were generated per sample. Respiratory viruses were detected in members of 52% (11/21) of families, including 6/10 (60%) families that had reported recent illness . ChildrePartial or full-length viral genome sequences with >80% coverage could be determined in 63% (22/35) of total detections. Among the samples for which depth of coverage could be calculated, the median depth of coverage was 89-fold , the putative detection of an additional virus (human parainfluenza virus 4b) was suggested by sequencing reads that mapped to an identical reference genome in the self-collected adult swab (F14-AS) and in the staff-collected child swab (F14-CR); however, in both cases, genome coverage did not meet previously established criteria for positive diagnostic identification.In this pilot, proof-of-concept study, we found that respiratory samples  self-collected from adults and children who were trained via online video and written instructions had comparable detection of respiratory viruses to samples concurrently collected by trained research personnel, with transport at ambient temperatures, as assessed by unbiased detection of respiratory viruses by NGS. All participants found the home collection procedures acceptable, and 85% reported minimal or no difficulty collecting the samples.Our findings are consistent with prior studies that have found home collection of anterior nasal swabs to be acceptable in general populations, with high levels of good-quality samples ,19-24. OWe considered any risk of nasal injury by self-collection to be minimal and outweighed by the potential benefit of understanding the feasibility and acceptability of self-collection of nasal samples for future research and public health surveillance. In one large, community-based study of over 4000 individuals given home collection kits with nasal swabs to be used on themselves or family members, there was one mild adverse event that did not require any medical attention and had no long-term impacts .This method could be applied to test exposed or symptomatic individuals without the need for visits to a health care facility during outbreaks of emerging respiratory viruses ,30,32. IThis study had several limitations. The sample size was small in this pilot study. Recent respiratory illness was self-reported and no information was collected about the duration of symptoms or the time between onset of symptoms and sample collection. It is therefore possible that individuals may no longer have been shedding virus at the time of sampling. Diagnostic performance of metagenomic sequencing was not compared to a reference method , although high agreement has been previously reported .We detected a diverse range of respiratory viruses, determined viral genome sequences in the majority of cases, and showed that viral genomes were identical in staff- and self-collected swabs. Our identification of a divergent strain of HRV-C with only 74% nucleotide sequence identity with the most similar known strain demonstrates the power of unbiased pathogen detection by metagenomics in the context of the well-described diversity of rhinoviruses ,36. ThisIn summary, our findings support a growing body of evidence that at-home nasal swab kits for viral detection can be reliably used, are well-tolerated, and provide a scalable solution for the detection and profiling of respiratory viruses. In addition to prior work showing the reliability of self-collected nasal swabs with PCR-based diagnostic tests, our findings suggest that self-collected nasal swabs can be reliable for shotgun RNA sequencing. As metagenomics is integrated into routine diagnostic workflows in a rapidly growing number of laboratories, pathogen genotypic information generated as part of diagnostic testing can be more easily shared and is likely to prove valuable in support of surveillance research and public health applications.


The prevalence of alcohol-related fatalities worldwide is on the ascendancy not only Ghana, but worldwide. Although the ramifications of alcohol consumption have been the subject of several studies, alcoholism remains a serious concern in public health. This study investigates the dynamics of alcoholism in a population with consumption-induced complications using a deterministic Modelling framework. Using a novel technique, we determined a threshold parameter  Besides, it was falsely recommended in 2019 that, alcohol was very effective in the treatment of corona virus (COVID-19) and this led to a lot of alcohol poisoning Mathematics has played an important role in researching into many disciplines. Among these are its application to disease control. Researchers have developed many mathematical models to predict and explain the effects of epidemics. However, the world still battles with a lot of diseases which are caused by either natural or artificial factors. All these explain why mathematicians have to do more research in building mathematical models to help reduce the risk of being exposed to epidemic diseases. Mathematical models have demonstrated high potential in helping to improve our knowledge of the dynamics of infectious agents and diseases. With alcoholism being a public health concern, many researchers have concentrated on building models to study the dynamics of alcoholism. Sa'nchez et al. We structure the remainder of the paper in the following manner: Section 2b. We define θ and they quit drinking alcohol at the rate of μ, In this section, the deterministic mathematical model of interest is developed to elucidate the dynamics of alcoholism with induced-complications. We categorize the population into five distinct and non-overlapping compartments: The compartment of Potential drinkers (P) denotes people who do not consume alcohol but are prone to adopting alcohol consumption behavior; Moderate alcohol abusers (M) represents individuals who slightly consume alcohol and have the ability to control the intake of alcohol; Heavy alcohol abusers (H) denotes people who are obsessive to alcohol consumption  and; Alcohol-abusers who have developed alcohol-induced complications (C) representing people who develop disorders such as liver cirrhosis, brain disorders, neuropathy complications, fibrosis, pancreatitis, and alcoholic hepatitis. We assume that all inflows into the population are Potential drinkers at the rate of The alcohol-abuse model described so far is thus presented by the following coupled ordinary differential equations.3It is easy to observe that the functions in the right-hand-side of The epidemiological and mathematical well-posedness of the model are presented in Theorem 3.1With non-negative initial conditions, the solution of the alcohol-abuse model(1)are always non-negatives for all time,.ProofImage 1 and Image 2, which contradicts our assumption. Therefore Assume that for some time  The set of epidemiologically-reasonable solutions of the alcohol-abuse model Lemma 3.1Future solution of the alcohol-abuse model(1)with non-negative initial conditions are all non-negative and contained in, which is positively invariant.ProofAdding all equations in Therefore, the solutions of the alcohol-abuse model 3.1The model The alcohol-abuse-free equilibrium given by basic alcohol-abuse initiation number. We define The basic reproduction number denoted as 3.2Theorem 3.2The alcohol-abuse-free fixed point,is locally asymptotically stable whenever. Otherwise,is unstable.The Jacobian matrix of the alcohol-abuse model Theorem 3.3The following conditions guarantee the local asymptotic stability of the alcohol-abuse-persistent fixed pointof model(1):The characteristic polynomial of 3.3In this brief, the global stability of the alcohol-abuse-free fixed point M, H and C, we use a Lyapunov function candidate give bySince the infected sub-system consists of Image 4Image 6 if Image 7 if and only if Image 8.Then Theorem 3.4The alcohol-abuse-free fixed pointof model(1)is GAS whenever.From the Lasalle's invariance principle 3.4Let The bifurcation coefficients are thus obtained  is increased, the number of potential drinker and moderate drinkers decrease (see The impact of the rate of transition from moderate to heavy drinkers was also studied by solving the model for varying values of the associated parameter, ease see b while tease see d. Thus, 6θ followed by probability of initiation per contact with a moderate drinker In this paper, we put forth a nonlinear differential equations model to elucidate the dynamics of alcoholism in a population. The population is split into five mutually-exclusive compartments of Potential drinker's moderate drinkers, heavy drinkers and individuals who have developed complications due to excessive consumption of alcohol. The model is developed by treating alcoholism as a contagion and following the theory of disease transmission from infected persons to Susceptible persons, consider the process of drinkers influencing non-drinkers as a transmission using standard incidence function. We adopted a recently developed technique There are multiple potential extensions of this study: The incidence functions have been shown to have interesting effect on the dynamics of models. While this work adopted a standard incidence function to describe initiation into alcoholism, future research could adopt saturated incidence functions as in Eric Abaa Baba Sandow: Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization. Baba Seidu: Writing – original draft, Formal analysis, Data curation, Conceptualization. Stephen Abagna: Writing – review & editing, Formal analysis.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Training and assessment of operator competence for the less invasive surfactant administration (LISA) procedure vary. This study aimed to obtain international expert consensus on LISA training (LISA curriculum (LISA-CUR)) and assessment (LISA assessment tool (LISA-AT)).From February to July 2022, an international three-round Delphi process gathered opinions from LISA experts  on a list of items to be included in a LISA-CUR and LISA-AT (Round 1). The experts rated the importance of each item (Round 2). Items supported by more than 80% consensus were included. All experts were asked to approve or reject the final LISA-CUR and LISA-AT (Round 3).A total of 153 experts from 14 countries participated in Round 1, and the response rate for Rounds 2 and 3 was >80%. Round 1 identified 44 items for LISA-CUR and 22 for LISA-AT. Round 2 excluded 15 items for the LISA-CUR and 7 items for the LISA-AT. Round 3 resulted in a strong consensus (99–100%) for the final 29 items for the LISA-CUR and 15 items for the LISA-AT.This Delphi process established an international consensus on a training curriculum and content evidence for the assessment of LISA competence.This international consensus-based expert statement provides content on a curriculum for the less invasive surfactant administration procedure (LISA-CUR) that may be partnered with existing evidence-based strategies to optimize and standardize LISA training in the future.This international consensus-based expert statement also provides content on an assessment tool for the LISA procedure (LISA-AT) that can help to evaluate competence in LISA operators. The proposed LISA-AT enables standardized, continuous feedback and assessment until achieving proficiency. Standardized simulation-based LISA education, including use of video laryngoscopy, has been recommended to improve LISA success rates.17 Nonetheless, to date, there is a lack of consensus on clinical practice and training required for gaining LISA proficiency.18 Therefore, clinicians would benefit from an internationally consented curriculum, based on sound clinical evidence and expert’s experience, that will serve as a template for LISA accreditation. Curriculum development should follow a structured approach starting with problem identification and a general needs assessment.20 Further, to support skills development, methods for assessment of LISA competence are needed to ensure high and consistent performance and to enable future mastery learning of the LISA procedure, where trainees practice with feedback until they achieve a predefined mastery learning level.22 This study aimed to provide international expert consensus on (1) the training curriculum for LISA operators and (2) what to include in the assessment of LISA competence.Less invasive surfactant administration (LISA) is a technique to administer surfactant to preterm infants with respiratory distress syndrome (RDS). LISA is performed by placing a thin catheter below the vocal cords of spontaneously breathing infants on non-invasive respiratory support.23 The survey questionnaires for Delphi rounds 1–3 are available from the corresponding author. We defined consensus in rounds 2 and 3 as an agreement of ≥80%. Figure From February to July 2022, we conducted a three-round iterative Delphi process using online survey questionnaires to collect information and establish consensus regarding the content to be included in 1) a LISA curriculum (LISA-CUR) and (2) a LISA assessment tool (LISA-AT) for the assessment of LISA competence. The Delphi process is a systematic, group facilitation technique using structured and semi-structured questionnaires to collect and organize the opinions from experts in the field until consensus is reached. a LISA cWe used the Research Electronic Data Capture (REDCap) system for data collection. Chinese experts could not access REDCap from mainland China and submitted their replies by e-mail. This information was subsequently entered into REDCap by the principal investigator (N.B.).The LISA experts were identified based on their involvement in research, curriculum development, and clinical education in the LISA procedure.Invitations to participate were sent via e-mail by the steering committee members using their professional networks. The initial invitation to participate was promoted by the European Society for Paediatric Research (ESPR) via its website, on social media, and in its newsletter. The invitation included a link to the online consent form and the survey questionnaire for round one. Participation was voluntary. All experts who participated in the first round were invited to participate in the following rounds.A Delphi steering committee was established to facilitate and manage all the steps in the Delphi process, including recruitment of experts and data analyses. The steering committee included an international team of 16 members with experience in neonatal intensive care or postgraduate medical education. All steering committee members except N.B. and M.G.T. were invited to participate in the survey due to their roles as international experts on the LISA procedure. The survey was developed by N.B. and piloted by the steering committee before the data collection in each round.List, in free text, the specific knowledge and skills that you believe a newly certified LISA operator needs to have and should be included in a curriculum for LISA training”, and (2) “List, in free text, all relevant aspects of the LISA procedure to be included in an assessment tool to evaluate competence/certification of a LISA operator.”The first round was a brainstorming phase where experts replied to the following statements: (1) “Experts provided baseline information, including sex, age, specialty, and years of experience with the LISA procedure and answered questions concerning local LISA procedure practice and use of training equipment.15 The remaining items were analyzed using content analysis24 to identify repeated categories of procedures and various textual expressions for each unique item to consolidate the lists for the LISA-CUR and the LISA-AT used in round 2. Due to variations in phraseology in round 1, the steering committee was allowed to adjust the wording but not the content of each suggested item. Decisions were based on 100% agreement within the steering committee.Data were gathered by N.B. and processed by the steering committee. Duplicates were removed. Teaching activities, learning-teaching strategies, and teaching methods were omitted as they were already described in other publications.Delphi round 1 were assessed for suitability for the LISA-CUR and the LISA-AT. The selection was based on importance by using a five-point Likert scale; (1) Not important at all, (2) Less important, (3) Neutral, (4) Important, (5) Very important. The experts replied to the following statements individually for each item: (1) “How important are the following items when learning how to perform the LISA procedure?” and (2) “How important are the following items when assessing the skill of an operator performing the LISA procedure?”In this round, items generated in the Delphi round 3.Items rated as important (4) or very important (5) by 80% or more of the experts were included in the preliminary LISA-CUR and LISA-AT that were sent back to the experts for final review and comments in The experts were informed about the distribution of scores, the excluded items, and selected comments from other experts in round 2. Subsequently, they were asked to approve or reject and comment on the preliminary LISA-CUR and LISA-AT.25 . Experts were informed about the aims of this study, the importance of participation, and the detailed tasks in each step of the Delphi process. All experts provided electronic informed consent prior to study participation. The datasets were de-identified prior to analyses. All information was handled confidentially. Data management and processing were approved (ID-number: P-2022-11). This study is reported according to the Consensus-Based Checklist for Reporting of Survey Studies (CROSS)Delphi round 1 are presented as frequencies (counts and percentages) and continuous data as medians with interquartile ranges [IQRs] and range as appropriate. Statistical analyses were performed using RStudio version 1.2.5001. There were no changes to study design after this study commenced. There was no imputation of missing data. The required response rate for each round was ≥70% to minimize non-response error.Categorical data from One hundred fifty-three experts agreed to participate in this study representing 14 countries worldwide   Complications, (3) Familiarity with the equipment, (4) Drugs and non-pharmacological measures, (5) Airway management, (6) Respiratory support, (7) Monitoring and assessment, (8) Evaluation, (9) Other skills  Delphi round 2 and returned to the experts for assessment.For the LISA-AT, 256 and 314 of the 658 items were excluded for the same reasons as those listed for the LISA-CUR. The steering committee further condensed the remaining 88 unique items to 22 and post hoc sorted all items chronologically in descending order from procedure start to finish .For the LISA-CUR, 12 items were eliminated by consensus  for each item to hopefully increase inter-rater reliability and provide more standardized assessments without restricting the use of the LISA-AT, as operators may perform very differently.The complete overview of adjustments to the LISA-CUR and LISA-AT between rounds 2 and 3 is available in the Online Supplement, Appendices E and F, respectively.Delphi round 3 was 83% (127/153 experts). The LISA-CUR and LISA-AT achieved consensus without changes . Furthermore, the rephrased item was included in the final assessment tool as 86% of the experts rated the item 4 (important) or 5 (very important).The response rate in In this Delphi process, 153 LISA experts from 14 countries were involved in a three-round iterative process to gather consensus regarding the training and assessment of LISA operators. Together, we developed the LISA-CUR consisting of 29 unique items, and the LISA-AT consisting of 15 unique items with response anchors. There are several benefits of implementing the LISA-CUR and LISA-AT in standardized training after adaptation to the local setting to increase operator competence and patient safety.18 has been a barrier to the implementation of LISA, as confirmed by experts’ in our study. Furthermore, the majority of the LISA experts in our study only performed 0–5 LISA procedures per month. Lack of formal training and infrequent clinical exposure to the LISA procedure may challenge adherence to clinical guidelines.26Until recently, a lack of formalized training14 So far, a consensus on a LISA training curriculum or assessment tool to evaluate operator competence has yet to be published. In 2021, Liebers et al.17 developed a LISA training program including multimedia materials, checklists, pocket cards, and team briefing, which increased the mean success rate of LISA from 62% to 92%, defined as no need for any of the following: intubation within the following 72 h, a second surfactant dose, or termination of the LISA procedure. In 2019, Vento et al.15 published a practical recommendation for surfactant administration specifying the characteristics of a trainer and a trainee and how training should be structured. Three training modules for operators and assistants were proposed, including (1) pre-course preparation and online test, (2) LISA training on a mannequin, and (3) post-course LISA consolidation by performing several procedures in the clinical setting with supervision combined with periodic refreshers on a mannequin. Recommendations by Vento et al.15 and Reynolds et al.27 suggest treatment thresholds, exclusion criteria, personnel, monitoring, equipment, non-pharmacological measures, and analgesics, including doses. The LISA-CUR may work with these existing recommendations to optimize and standardize LISA training in the future.A combination of theoretical aspects with practical training for learning the LISA procedure is recommended.15 and Reynolds et al. (2021)27 also identified core items that an operator should be able to undertake, but these reflected the individual opinions of the clinicians involved in formulating the recommendations. All their core items were included in the LISA-AT we propose and are now supported by international expert consensus. Various techniques for the LISA procedure exist,15 which may explain the lack of consensus achieved for various procedure-specific items like catheter type, Magill forceps, checking for gastric retention, and lung ultrasound, which were excluded from the final LISA-CUR and LISA-AT. These procedural factors clearly should be a focus of future research. Local protocols for each procedure step must exist before the LISA-CUR and LISA-AT can be adapted to the local setting and successfully implemented. Since this is first of a kind initiative, opinions may be inconsistent and further validation of the tool will help to refine it.The consensus-based LISA-AT consists of 15 unique items and may provide standardized feedback, assessment, and potential certification of LISA operators. Vento et al. (2019)Development of the LISA-AT is the first step to enable mastery learning through standardized, continuous feedback and assessment until a predefined performance criterion is achieved.21 To our knowledge, there is no pre-defined mastery learning level, and we do not know how much practice is needed during simulation-based LISA training to reach sufficient levels of mastery.28 Future studies need to validate the LISA-AT using Messick’s framework,29 which is the gold standard when evaluating validity as the American Educational Research Association recommended in their Standards for Education and Psychological Testing.31 Following validation, NICUs and neonatal simulation centers may standardize LISA training and assessment by implementing the LISA-CUR and LISA-AT. This should be a necessary step before the operator is promoted from training in the simulated environment to training in the clinical setting.However, there is currently no validity evidence to support the use of the LISA-AT and its ability to differentiate between operators with different levels of experience.32 We minimized the risk of conflict of interest and group pressure frequently associated with expert panels by anonymizing all responses prior to analyses and providing a unique link for each expert per round.33 This study was conducted following a detailed protocol (available from NB upon request) with no changes to the study design after the initiation of round 1, limiting individual members’ influence through all three rounds. Hence, only items achieving the predefined consensus cut-off were included in the final LISA-CUR and LISA-AT. Due to the online advertisement through the ESPR website, we are unaware of the total number of potential experts who might have seen the invitation. We are also unaware of the actual number of participants recruited by the online advertisement and the reasons for non-participation at each stage. However, we minimized the risk of bias from lack of response by achieving response rates of more than 80% of the initial responders in Delphi rounds two and three. Multiple NICUs contributed data from each country, minimizing the risk of bias arising from multiple responses from a single institution. No single country was represented by more than 15% of all the experts in our study. We chose a broad set of inclusion criteria for LISA experts to gather as many inputs as possible. Although this might have diluted the qualification of being an “expert,” baseline data showed that 97% of experts were board-certified neonatologists involved with the LISA procedure for several years. The experts involved in this study represented highly specialized NICUs from Western and non-Western countries. However, some NICUs may not have the resources to improve training and assessment for the LISA procedure, as this procedure is just one part of a resource-demanding intensive care strategy for preterm infants.The Delphi research method is ideal for studying which items to include in the LISA-CUR and the LISA-AT when objective information is unavailable.This Delphi process generated international consensus on a LISA curriculum (LISA-CUR) and a LISA assessment tool (LISA-AT). The LISA-CUR and LISA-AT are published with this study and may be used by LISA trainers, supervisors, and curriculum developers to guide their efforts.APPENDIX AAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DAPPENDIX E


Introduction of vaccines against COVID-19 has not encountered expected acceptance. The uptake of COVID-19 vaccines in Western Balkans countries is lagging behind the European Union average. The aim of our study was to assess the intention to get vaccinated against COVID-19 in the population of unvaccinated adult citizens of five Western Balkans countries, and to explore factors that influence the vaccination intention.Cross-sectional study was conducted in the period from July to October 2021. The questionnaire was shared through online social media. Intention to get vaccinated against COVID-19 was measured by a single item assessing the likelihood of getting vaccinated on a 5-points Likert scale. Linear regressions were conducted with socio-demographic characteristics, presence of chronic diseases and attitudes towards COVID-19 vaccination as independent factors.The largest proportion of unvaccinated respondents willing to get vaccinated in the future was observed in Montenegro and Albania (40.4% in each country), while in the Serbian sample, the willingness to get vaccinated was the lowest (22.6%). Socio-demographic characteristics were not significantly associated with the intention to get vaccinated against COVID-19 in most of the countries. In Albania, Bosnia and Herzegovina, North Macedonia and Serbia the strongest determinant of COVID-19 vaccination intention was the higher sense of social responsibility.Vaccination interventions and campaigns aiming to improve the COVID-19 vaccine uptake should be focussed on specific set of factors in each country, appealing to social responsibility as most prevalent determinant of vaccination intention in Western Balkans. Numerous studies have explored factors that influence people’s decision to get vaccinated, using different methodologies and presenting different strength of evidence.The uptake of COVID-19 vaccines in Western Balkans countries is lagging behind the European Union (EU) average. According to the last available official data the proportion of population fully vaccinated (with two doses) against COVID-19 is 40% in North Macedonian, 44% in Albania, 48% in Serbia, 45% in Montenegro and 26% in Bosnia and Herzegovina, which is far below the proportion of 73% in the EU.As part of a larger project investigating COVID-19 related vaccine hesitancy in Western Balkans, this cross-sectional study was conducted in the period from July to October 2021. Adult citizens over the age of 18 from the five Western Balkans countries  were included. Convenience, non-probability sampling was applied. Data were collected by means of the online questionnaire, using the SurveyMonkey platform, which automatically saves digital responses to a database. The questionnaire was shared through widely used online social media (Facebook and Instagram), using targeted posting method. Individuals could access the questionnaire link by clicking on the post. It took ∼15–20 min to complete the questionnaire. Intention to get vaccinated was analyzed in the sub-sample of unvaccinated respondents, since vaccinated already manifested their intention.The questionnaire was developed for the purpose of this study based on the literature.The primary outcome—‘intention to get vaccinated against COVID-19’ was measured by a single item assessing the likelihood of getting vaccinated on a 5-points Likert scale (ranging from 1—extremely unlikely to 5—extremely likely);Socio-demographic characteristics included six items: gender, age, education level, employment status (employed/self-employed/unemployed), financial status (very good/good/average/bad/very bad) and religiosity (yes/no);Existence of the chronic health conditions was assessed by the single question ‘Do you suffer from any chronic disease?’ with the binary (yes/no) response;Seven short scales measuring different attitudes related to COVID-19 vaccination, on a 5-point agreement Likert scales (ranging from 1 ‘strongly disagree’ to 5 ‘strongly agree’). The total score for each scale was calculated by summing the responses to all items, and dividing that sum with the number of items. Items with negative connotation were reversely coded when calculating the total scores. The total score range for each scale was divided in four quartiles: 1–1.99 (highly negative), 2–2.99 (moderately negative), 3–3.99 (moderately positive) and 4–5 (highly positive). Items of each attitude scale are presented in the α ranging from 0.52 to 0.93 across country samples).– Attitudes towards vaccine efficacy .– Attitudes towards vaccine safety .– Attitudes towards compulsory vaccination .– Attitudes towards danger of COVID-19 disease .– Attitudes towards COVID-19 susceptibility . Social responsibility .– Trust in societal factors  and Overall, 1605 of respondents fully completed the questionnaire. Socio-demographic and health-related characteristics of respondents per country are presented in Respondents from five surveyed countries differed in their attitudes towards COVID-19 vaccination . In all Intention to get vaccinated was explored in the sub-sample of 700 respondents from the five studied countries who declared to be unvaccinated, since vaccinated respondents already manifested their positive intention. At the time of conducting the study third and consecutive doses of the vaccine were not an option.In the total sample of unvaccinated respondents, 13.9% will certainly and 18.5% will probably get vaccinated in the future, while 20.8% were unsure. Almost half of the respondents (46.8%) probably or certainly did not intend to get vaccinated. The largest proportion of unvaccinated respondents willing to get vaccinated in the future was observed in Montenegro and Albania (40.4% in each country), while in the Serbian sample the willingness to get vaccinated was the lowest (only 22.6% reported they would probably or certainly get the vaccine in the future) .The propThe results of multivariate regression analyses are presented in ,,This study is among the first research examining attitudes towards COVID-19 vaccination and the intention to get vaccinated against COVID-19 in Western Balkans countries, contributing to the large number of studies exploring COVID-19 vaccination intention worldwide.Results of our study suggest that socio-demographic characteristics might not be particularly relevant factors of vaccination intention. Only younger age in Montenegrin sample was significantly associated with the stronger intention to get vaccinated against COVID-19. Similar to our findings, in a study conducted in Italy no significant association was found between socio-demographic variables  and vaccination intention.,,,,,The results obtained in this study indicate that, in general, respondents in Serbia, Albania, Bosnia and Herzegovina, North Macedonia and Montenegro moderately believed that COVID-19 vaccine administration is the beneficial and safe intervention to successfully reduce the disease and that COVID-19 vaccine is harmless. Respondents in all five countries estimated that there is a moderately strong danger of COVID-19 in general, at the same time assessing that their personal risk to get sick was moderately high. It was observed that confidence in political and health authorities, science, and pharmaceutical companies was moderate, while personal sense of responsibility in achieving collective immunity and contagion prevention was moderately high  and high (in North Macedonia).Our results obtained in Serbia, Bosnia and Herzegovina and Albania partly confirm previously established associations of vaccination intention with vaccination attitudes towards efficacy and safety, perceived risk of infection and disease severity.,Interestingly, in respondents from Serbia, Bosnia and Herzegovina, Macedonia and Albania social (collective) responsibility showed to be the strongest predictor of vaccination intention similarly to the studies from China and UK suggesting that collective responsibility (e.g. vaccinating oneself to help maintain herd immunity) may be facilitating vaccination uptake.Although this study presents valuable evidence on COVID-19 vaccination intention in the population of Western Balkans, several limitations should be discussed. First, we sampled respondents through online channels, which excluded people who are not internet users. Online surveying was a method of choice since face-to face survey was not feasible due to the high rate of COVID-19 transmission during the study period. Second, convenience sampling does not provide sufficient level of representativeness. Third, since we employed cross-sectional design, causal relationships between variables cannot be established. Future studies with probability sampling and face-to-face distribution of questionnaires are needed to establish more general conclusions.Results of this study suggest that vaccination interventions and campaigns aiming to improve the COVID-19 vaccine uptake should be focussed on specific set of factors in each country, promoting confidence in vaccine efficacy and safety and appealing to collective responsibility as most prevalent determinants of vaccination intention in Western Balkans. Interventions should be context-relevant, integrated, multi-component and based on risk communication, community engagement and social mobilization to increase trust and social cohesion resulting in increased COVID-19 vaccine acceptance among all stakeholders.ckad066_Supplementary_DataClick here for additional data file.


Spiking neural networks (SNNs) are a model of computation that mimics the behavior of biological neurons. SNNs process event data (spikes) and operate more sparsely than artificial neural networks (ANNs), resulting in ultra-low latency and small power consumption. This paper aims to adapt and evaluate gradient-based explainability methods for SNNs, which were originally developed for conventional ANNs.The adapted methods aim to create input feature attribution maps for SNNs trained through backpropagation that process either event-based spiking data or real-valued data. The methods address the limitations of existing work on explainability methods for SNNs, such as poor scalability, limited to convolutional layers, requiring the training of another model, and providing maps of activation values instead of true attribution scores. The adapted methods are evaluated on classification tasks for both real-valued and spiking data, and the accuracy of the proposed methods is confirmed through perturbation experiments at the pixel and spike levels.The results reveal that gradient-based SNN attribution methods successfully identify highly contributing pixels and spikes with significantly less computation time than model-agnostic methods. Additionally, we observe that the chosen coding technique has a noticeable effect on the input features that will be most significant. These findings demonstrate the potential of gradient-based explainability methods for SNNs in improving our understanding of how these networks process information and contribute to the development of more efficient and accurate SNNs. Conventional neural networks, also known as artificial neural networks, although proven to be useful for numerous tasks, have latency, energy and storage requirements that may not be adequate for many real-time tasks in energy-constrained environments. The field of neuromorphic computing, inspired by the efficiency of biological neural networks, attempts to replicate this efficiency through brain-inspired models of computation such as SNNs Maass, .spikes   model Gerstner et al.  method  through (a) spike encoding, (b) spike-attribution map generation, and (c) mapping from spike-attribution map to an attribution map of the input. These methods are referred to as post hoc existing approaches for SNNs.We qualitatively assess our methods through visual inspection, giving an insight on how SNNs classify with different neural encodings and demonstrate through quantitative perturbation analysis that the resulting attribution maps for both spiking event-based data and real-valued 2D images are quantitatively superior to the alternative membrane potential. As the membrane potential reaches a critical threshold, the neuron fires a spike to the next connected neurons and the potential is reset. A positive membrane potential is continuously reduced, or leaked, so the timing of the incoming spikes is critical. SNNs aim to reproduce these properties of biological neurons using differential equations for the neuron models and consuming and producing spiking data rather than floating point numbers as in conventional ANNs. As the spiking neurons only propagate spikes after integrating multiple incoming spikes, data passed through the SNN is sparse, and thus a great number of neurons remain silent during a forward pass. These are the main reasons for the sparsity and energy-efficiency of SNNs. Please refer to the Spiking neural networks are biologically inspired neural networks, which possess similar topology as artificial neural network but differing in terms of base neuron units. Information is transmitted across neurons through the synapses connecting pre- and post-synaptic neurons. Incoming spikes are integrated into the neurons' Unsupervised learning based on timing causality of pre- and post-synaptic spikes: if an input spike preceded an output spike it probably had a causal relationship. STDP has been successfully used to train a variety of shallow SNNs  for neural networks, we restrict the discussion solely to input attribution and layer activation methods for image data, and present the existing XAI methods for spiking neural networks. XAI methods can be divided into two categories; (i) model-agnostic and (ii) model-specific methods.LIME  gradient-based approaches, such as Saliency Maps . Both methods produce activation maps for SNNs, i.e., which input regions triggered a layer the most. The former uses backprop up to the convolutional layer of interest, while the latter only forward propagates the effect of a spike to successive layers. Afterwards, the activation maps at particular convolutional layers can then be scaled to the input image size for superposition. These two approaches to create visual 2D feature maps are however limited to convolutional layers. In this work, we evaluate through input perturbation experiments the efficacy of SAM as a tool to obtain input attribution maps as Kim and Panda   had to be trained to learn that relationship, and GradCAM introduced gradient back propagation to estimate an attribution map from pure activations. Furthermore, a better model-specific attribution method will also allow to avoid the huge cost of model-agnostic computational combinatorial explosion.The experiments in this study were conducted using two datasets: Cifar 10 and DVS128 Gesture Dataset.Cifar-10  and SNN-IG (Integrated Gradients) to obtain spike-level and pixel-level attribution maps. For all methods, to compute the gradients through the post inference backward pass, we use a surrogate-gradient approach, as the spiking function is non-differentiable and thus an approximation is necessary.Based on established gradient-based pixel-attribution methods for Saliency maps, first introduced by Simonyan et al. , computeSNN-Grad3D similarly to the original Saliency Map  as the sum of spikes per output neuron. Indeed, the classification decision of an SNNs output is usually decided by the most spiking output neuron. Thus output neuron with the highest number of spikes is naturally the winning class. We define our SNN-Grad3D map to represent the gradients of the class score (SC) with respect to the input. Using the surrogate-gradient, for an image of size height×width encoded in t timesteps, we obtain a spike attribution map of size height×width×t indicating how much would the class score SC change if a spike could be added or removed at any point in this 3D space.We define our SNN-Grad3D is simply combined with a mapping strategy (Section 2.4.3), to reduce the temporal dimension.To obtain an attribution map for 2D images small variations of the input. It achieves this by first creating a monotonous path from a baseline input to the original input in n_steps. IG is then computed by integrating gradients along this path.The second set of proposed gradient-based attribution methods, are an adaptation of the Integrated Gradients . However, recall that the information is encoded across spikes in the timing between the spikes. For this work, we adapt IG into two SNN-Crafted IG versions depending on the original input: 2D image (SNN-IG2D) and event-based sensor (SNN-IG3D).As event stream inputs are binary timeseries, intermediary steps between “off” and “on” spikes do not exist, thus a path cannot be created by Leveraging our knowledge of the original 2D input data, similarly to Integrated Gradients , we create a path from an empty 3D event stream, to the original input event-data sequence by sampling timesteps from the original event-data input with iteratively increasing sampling-rate along the path, up to the complete original event stream over SNN-Grad2D and SNN-IG2D, which was the summation across time for both. Further mappings and their equations can also be found in the To close the explanation loop for real-value input data, a mapping from the spike-level attribution-box to the original input space is necessary see . For 2D In this subsection, we introduce Inverted SAM (ISAM), a modified version of the SAM method used in the perturbation experiments for interpreting the encoded event stream. ISAM aims to enhance the attribution mapping performance specifically in the context of spiking neural networks.ISAM is derived by taking the negative of the SAM scores obtained from the convolutional layers of the SNN. This inversion of scores provides an alternative perspective by highlighting regions that are deemed less important or influential in the decision-making process of the SNN. By utilizing ISAM, we can explore the impact of suppressing or removing specific spikes on the overall performance of the SNN.The application of ISAM in our experiments shows promising outcomes, which motivates further investigation into its effectiveness and implications. Understanding the underlying reasons behind the observed performance improvements and the characteristics contributing to its efficacy at different layers requires more in-depth analysis.This section of the paper presents the details of the spiking neural network architecture and training as well as the evaluation process used in our study. In Section 2.6.1, we describe the SNN architecture and training methodologies used for image classification tasks. We also present the parameters used for training the SNNs and how the networks were trained. In Section 2.6.2, we describe the evaluation process used to evaluate the performance of the SNNs, as well as the metrics used to measure the performance of the SNNs and the XAI methods. This section provides a comprehensive overview of the experimental setup used in our study and will enable readers to reproduce the results presented in this paper.LeNet-5  ~1.54 s, SAM ~8.39 s, RISE ~13.27 s and LIME ~49.78 s. See The average latency overhead to compute 2D attribution maps for 100 samples of the CIFAR-10 image with Deletion (Insertion) experiments, as used in Samek et al. (k most important features—spikes or pixels—based on the attribution map are removed (inserted), and the degradation (improvement) of the classification score and class recall accuracy are iteratively recorded. We perform these perturbation experiments on a subset of 600 samples of the validation data sets that the network correctly classified, to avoid a doubtful correctness evaluation of an attribution map obtained from wrong predictions. Perturbation of features means changing it to some predetermined value (the baseline). The choice of baseline is an important factor to keep in mind when evaluating attribution methods, as it can create some artifacts, which confuse the models as seen in Samek et al.  and random perturbation as baseline. Our gradient-based methods produce positive or negative attribution scores. We evaluate our methods with both the raw score, or with the absolute value (postfix ABS) as commonly done in the equivalent XAI related work for ANNs.In SAM  performs worse than random. SAM captures neuronal activity at convolutional layers, but results indicate that this activity map does not directly translate to a true input attribution map. This matches our expectation of the non-linear relationship between activation and attribution. We decided to evaluate the inverted version ISAM (the negative of SAM scores), and its performance surpassed the random baseline. Our method SNN-IG2D(ABS) performs better than SAM in both perturbation experiments. Remarkably, inverse SAM at layers 3 and 5 do better in spike removal and competitively in spike insertion. We speculate that the SAM attention maps are in this case indicative of a dominant sensory suppression behavior  quickly identifies important features, which rapidly, with about 5% of spikes, increase the SNNs performance to around 50% accuracy in classifying the data. At around 30% insertion, SNN-Grad2D(ABS) and ISAM at layer 3 overtake SNN-IG2D(ABS). The reason behind this behavior and why ISAM at layer 3 performs better than a later or an earlier layer is not clear to us.In spike perturbations , B, SAM SNN-Grad2D, SNN-IG2D (on three baselines) and SAM, ISAM using summation mapping to obtain 2D attribution maps, as well as the model-agnostic methods RISE  performs the best among the model-specific methods. It is possible that our methods did not outperform model-agnostic ones in part due to the simplistic mapping across the time dimension. For pixel removal, the black baseline produces better results, while in pixel insertion a gray baseline is better. This can intuitively understood: removing a pixel with the lowest value (black) is a stronger perturbation than “removing it” with a bright value (white). Similarly, inserting a few important features in a completely empty (black) background is a significant deviation from the training data distribution, thus a gray baseline recreates a closer sample of the training distribution.In pixel perturbations, the model agnostic methods are capable to identify important features quite well and justify their high computation cost. Both SNN-Grad3D and SNN-IG3D methods on event-based data, using the same perturbation strategy.We evaluate our SNN-IG3D, using the spike sampling (ii) of SAM method. The original SAM method now is better than the inverse ISAM at all layers. In the previous experiment, as better appreciated in SNN-IG2D and SNN-IG3D get better results in all out experiments in the ABS case. The SNN-Grad3D signed version is better for both insertion and deletion and SNN-Grad2D is significantly improved by taking the absolute value in all but the spike removal experiment, where it moderately decreases. This behavior seem to be related to the difference of information carried by each method. Gradients capture very local behavior, so big local negative change is not necessarily the same as indicating that the pixel is not a positive influence.As seen in Explainability of SNNs poses unique challenges, requiring specialized methods to understand their decision-making processes. In this paper, we have investigated the effectiveness of gradient-based attribution methods for SNNs trained with the surrogate backpropagation approach.SNN-Grad2D, SNN-Grad3D, SNN-IG2D, and SNN-IG3D, offer several advantages over existing approaches. Firstly, these methods require significantly less computation time compared to other techniques. Secondly, they are not limited to convolutional operations as methods producing activation maps, which enhances their applicability to various neural coding schemes. Thirdly, unlike deconvolutional methods, they do not necessitate training an extension of the model. Lastly, the perturbation experiments demonstrate that these methods provide true attribution scores.Our findings indicate that gradient-based methods, namely While discussing the preference between Integrated Gradients and Gradient methods, it is worth noting that SNN-IG has shown particular superiority. SNN-IG excels in providing finer-grained attribution maps compared to model-agnostic or activation-based methods for SNNs. The integration of gradients along the input space, as employed by SNN-IG, enables a more comprehensive understanding of the influence of different input features on the SNN's decisions.In future work, we envision several avenues for enhancing Explainable Neuromorphic Computing. Firstly, it would be valuable to refine the surrogate-gradient approach to mitigate inaccuracies that may impact gradient-based methods. This would further improve the reliability and interpretability of the attribution maps generated. Secondly, exploring the adaptation of other gradient-based eXplainable Artificial Intelligence methods from ANNs to SNNs could provide valuable insights and potential advancements. Lastly, developing specific mapping techniques based on neural codings to accurately map 3D attributions back to the pre-encoded source data would enhance the interpretability of SNNs operating on event-based inputs.Overall, this study contributes to the understanding of explainability in SNNs and opens up avenues for future research, bridging the gap between neuromorphic computing and interpretable artificial intelligence.The original contributions presented in the study are included in the article/AB and RR contributed to conception and design of the study and wrote sections of the manuscript. AB organized the database, performed the statistical analysis, and wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.


Freshwater acquisition methods under various environments are required because water scarcity has intensified worldwide. Furthermore, as water is an essential resource for humans, a freshwater acquisition method that can be utilized even under harsh conditions, such as waterless and polluted water environments, is highly required. In this study, a three-dimensional (3D) printing-assisted hierarchically structured surface with dual-wettability  for fog harvesting was developed by mimicking the biological features  that have effective characteristics for fog harvesting. The cactus-shaped surface exhibited self-transportation ability of water droplet, derived from the Laplace pressure gradient. Additionally, microgrooved patterns of the cactus spines were implemented using the staircase effect of 3D printing. Moreover, a partial metal deposition method using wax-based masking was introduced to realize the dual wettability of the elytra of the Namib Desert beetle. Consequently, the proposed surface exhibited the best performance (average weight of 7.85 g for 10 min) for fog harvesting, which was enhanced by the synergetic effect between the Laplace pressure gradient and surface energy gradient. These results support a novel freshwater production system that can be utilized even in harsh conditions, such as waterless and polluted water environments. Furthermore, although water is an essential resource for human life, the amount of freshwater available to humans depends on the geographic location  and the water supply infrastructure3. To address this problem, several works to obtain freshwater, such as fog harvesting6, desalination8, membrane filtration10, and solar-driven water production11, have been conducted. Fog harvesting, which can capture atmospheric water, is an attractive method that can be used even in arid  and polluted water environments12. Moreover, compared with other methods, fog harvesting has the advantage of not only having no location restrictions but also rapid on-site production13. In nature, various biological features to obtain freshwater in harsh environments can be found, such as cactus spines14, silk of spider15, elytra of Namib Desert beetle16, and inner wall of nepenthes17. Cacti and Namib Desert beetles are representative desert creatures that collect water from the atmosphere in harsh environments. Cactus can effectively collect water from fog in the desert using microgrooved patterns on its spines18. Specifically, the spines of the cactus have self-water transportation and water collection abilities derived from the Laplace pressure and wettability gradients19. The Laplace pressure gradient allows the collected droplets to be self-transported from the tip to the base of the spine20. Additionally, the wettability gradient derived from the grooved surface enhances the surface wettability 14. Moreover, the Namib Desert beetle has water collection and self-transportation abilities induced by the surface energy gradient from the dual wettability  on the elytra surface21. Water droplets from fog preferentially condense on hydrophilic bumps, whereas water droplets condensed on hydrophobic valleys are transported to hydrophilic bumps via a surface energy gradient22.Currently, water scarcity has intensified because the existing water supply has not satisfied the demand for water owing to the increase in global population26 or the spine of the cactus29. To manufacture a fog-harvesting surface inspired by the elytra of the Namib Desert beetle, methods to realize coexisting hydrophobic and hydrophilic regions have been demonstrated using taping31, film masking32, and inkjet printing33. Because taping and film masking require additional masks, these methods are not suitable for mass production if the masking area has a complex morphology. Although inkjet printing does not require a mask, it cannot be applied to complex morphologies. Manufacturing methods to fabricate fog-harvesting surfaces inspired by the spines of cacti have been recently demonstrated using laser drilling34, CNC machines35, immersed surface accumulation-based three-dimensional (3D) printing36, and photolithography37. Although the morphology of the cactus spine is well understood, most methods involve high costs, complicated processes, and specialized equipment. Moreover, most fog-harvesting surfaces inspired by the cactus spine mimic only the conical structure, except for the microgrooved patterns of the cactus spine. Unlike the aforementioned manufacturing methods, fused filament fabrication (FFF)-type 3D printing technology offers the advantages of low cost, rapid prototyping, and simple manufacturing38. However, FFF-type 3D printing has a chronic drawback of the staircase effect caused by stacked filaments39. Therefore, hierarchically structured surfaces with various designs can be effectively realized using the staircase effect of FFF-type 3D printing.Inspired by these biological features, various surfaces for fog harvesting have been designed to mimic the elytra of the Namib Desert beetleIn this study, a novel manufacturing method for hierarchically structured surfaces with dual wettability was demonstrated for fog (water) harvesting applications. The hierarchically structured surface for water harvesting was designed by mimicking not only the conical structure with a microgrooved pattern of the cactus spine, but also the dual-wettability of the elytra of the Namib Desert beetle, as illustrated in Fig. To demonstrate the effects of wettability and hierarchical structures, six different types of water-harvesting surfaces were designed and defined , side-view optical images of the hierarchically structured surfaces were obtained every 10 s during fog harvesting. As shown in Fig. To investigate the effects of the parallel-aligned microstructured layer of the bottom region during water harvesting, sequential optical images of the hierarchically structured surfaces along two directions  were obtained every 12 s. Two directions (-L and -T) were set according to the L and T directions of the aligned microstructured layer toward the water container. As depicted in Fig. For the quantitative analysis of the proposed surfaces along different directions, the time-dependent weight and total weight of the collected water were obtained, as shown in Fig. To demonstrate the main factors, i.e., Laplace pressure gradient, surface area, and drainage efficiency, of the water harvesting performance of BI-L, three parameters  of BI-L were considered. To compare and analyze the fog harvesting performance of surfaces by three factors, seven types of surfaces  were designed and prepared. To ensure identical wettability conditions of the prepared surfaces, the hydrophobic region was fixed at a height of 3 mm in the tip region of the conical structures. The detailed type and geometry information of prepared surfaces to demonstrate the main parameters were listed in Table To compare the performance of surfaces with fixed diameter of conical structures, three types of BI-L with different distances between conical structures and number of conical structures  were utilized, as shown in Fig. To compare the performance of surfaces with fixed distance between conical structures and number of conical structures, three types of BI-L with different diameters and number of conical structures  were used, as depicted in Fig. In this study, a hierarchically structured surface with microgrooved patterns was fabricated using FFF-type 3D printing. The proposed surface was designed to mimic the morphology of the cactus spine and dual wettability of the Namib Desert beetle. Microgrooved patterns of the cactus spine were implemented on the cactus-shaped PDMS surface using the staircase effect of FFF-type 3D printing. To realize the dual-wettability of Namib Desert beetles, a partial Pt deposition method using a paraffin wax-based masking method that enables mass production of complex morphology was introduced. Because of the surface energy gradient, although the hydrophobic region can condense more water droplets than the hydrophilic region, the condensed water in the hydrophobic region can be self-transported to the hydrophilic region. Furthermore, the cactus spine morphology enables condensed water droplets to self-transport from the tip to the base region using the Laplace pressure gradient. Moreover, the microgrooved pattern not only guides the water in a certain direction but also enhances surface wettability with an increase in surface area. To demonstrate the effects of conical structure and wettability in the fog-harvesting performance, qualitative and quantitative analyses were performed using six different types of surfaces under the same conditions. Consequently, the surfaces with conical structures exhibited higher fog harvesting performance than flat surfaces. It should be noted that the fog-harvesting performance of BI-L increased by approximately 123% compared to that of FO. Furthermore, among the surfaces with conical structure which has only difference with surface wettability condition, BI-L (D3S1) exhibited the highest performance  using the fog-harvesting performance enhancement method . In addition, the effects of three main factors  in the fog-harvesting performance were demonstrated using BI-L with the variations of three main structural parameters . Note that, D2S1 exhibited the best performance  compared with the other surfaces  because of the proper combination of the Laplace pressure, surface area, and drainage efficiency. Namely, the fog harvesting performance of proposed surface can be more enhanced by newly deriving a proper combination of three main structural parameters . These results support an effective fog-harvesting surface that enables freshwater to be obtained even under harsh conditions, such as arid and polluted water environments.Supplementary Information.