Team development and idea generation are key intertwined steps in translational science that need a framework to accommodate unstructured, participatory interactions. To this end, we introduced Un-Meetings to the Clinical and Translational Science Awards (CTSA) Program, innovative events that facilitate cross-disciplinary idea generation and informal discussions between translational scientists, policy makers, community members, advocates, and public health professionals. Here we describe a mixed methods study to characterize the conceptual diversity and clusterization of ideas generated through an Opioid Crisis Un-Meeting.An Un-Meeting targeting translation science approaches to the opioid crisis were hosted at the University of Rochester Center for Leading Innovation and Collaboration (CLIC). We used semantic analysis and conceptual mapping of keywords to analyze how attendee-led idea generation sessions identified topics for breakout discussions.One hundred and two individuals from 40 institutions proposed 150 unique ideas that were grouped into 23 breakout sessions. Network analysis showed that diverse pools of experts were bridged by topics addressing the complexities of the opioid crisis. Two clusters emerged: (1) systems, contexts, and community engagement, and (2) technologies, innovations, and treatment advancements.The cross-disciplinary nature of topic areas that bridge across thematic communities provide opportunities for CTSA programs to engage and support development of diverse translational teams. Potential opportunities for team building include technological advancements of opioid prevention, treatment, surveillance, systems approaches, and studies focusing on special populations and health disparities. The analysis method here may be useful in identifying naturally emerging teams of experts and community gaps when addressing large problems. Translational research involves bridging between different stages of the translational spectrum  to find, test, and implement solutions that address complex biomedical and health problems . InnovatUn-conference is an innovative meeting that shifts from traditional didactic lectures and presentations to a more participatory format that engages attendees from multiple disciplines to co-develop ideas and form collaboration networks [The networks . Un-confnetworks ), which networks ,9.The University of Rochester Center for Leading Innovation and Collaboration (CLIC), the National coordinating center for the National Institutes of Health Clinical and Translational Science Awards (CTSA) Program, adapted the methodology of Un-conferences  to develThe unstructured format of the Un-Meeting allows researchers to form social clusters that may lead to early transdisciplinary team formation. In addition to formal organizational affiliations (e.g. institutions and departments), invisible communities of research and collaboration can form based on shared interests, values, and scientific worldviews that cross traditional organizational structures. These “invisible colleges” , “invisiThe data collected through an Un-Meeting provide a unique opportunity to study the emergence of translational ideas for future research from the perspective of investigators interested in developing emerging collaborations, and to identify potential invisible research communities. Previous efforts identifying such ideas and communities have been largely limited to semantic analysis of translational research topics, heavily focused on bibliometric analysis of research outputs to identify hot topics and emerging fields  or commIn contrast, analytic clustering of dynamic Un-Meeting topic keyword data allows a multifaceted analysis of attendee interests, dominant fields, and common frameworks. Such keyword analysis may identify bridging topics and cross-disciplinary approaches for future scientific team formation to address urgent research problems. Network analysis can identify topics that connect attendees from disparate research areas, similar to identifying bridging keywords in research publications that cross scientific fields –24.In this exploratory study, we describe content analysis of topics generated by participants in an Un-Meeting on the “opioid crisis” at University of Rochester. We investigated the clustering patterns and bridging action words, as indicators of dominant fields and bridging opportunities.The Center for Leading Innovation and Collaboration (CLIC), housed at the University of Rochester, hosted the first CTSA-wide “Un-Meeting” on June 2, 2018 addressing the opioid crisis. The Un-Meeting is a participatory event focused on engaging translational scientists, policy makers, community members, advocates, and public health professionals in a dynamic process of idea generation and translational conversation . The Un-After the talks, attendees used sticky notes to write topics of interest, questions, or ideas for breakout sessions and placed them on an idea generation board. Assisted by the organizing team, conference participants were encouraged to group the ideas into common themes that would determine the eventual topics for the subsequent concurrent small group breakout sessions. Facilitators and participants re-arrange and aggregate these notes into small group session topics in specific rooms and time slots. Attendees then self-select which sessions they would like to join. The resulting breakout sessions were 45 minutes long, unmoderated, and included between 8 and 25 participants. A second round of 4×4 talks, topic generation, and breakout sessions occurred in an afternoon session.Photographs of the notes posted on the grid were used to collect the final clustering, and were transcribed into machine-readable format by hand. Each note was treated as a separate unit of text and was pre-processed by removing stop words  and common terms using the Automap program . The resWe used two analytical techniques to explore the patterns of topic clusterization:Keyword cluster analysis: We clustered keywords based on their co-occurrence in notes and linked them with their corresponding breakout sessions using a density-based spatial clustering (DBSCAN) algorithm [lgorithm  with a cKeyword-to-session network mapping: To identify keywords that bridged across fields and disciplines, we performed a separate analysis on keywords that were assigned to more than one breakout session. We expected that this analysis would provide clues to translational opportunities to address the opioid crisis and opportunities for cross-disciplinary team formation. We developed a keyword-to-session two-mode matrix and map, with nodes representing keywords and breakout sessions, and edges representing the relation between keywords and sessions. The nodes (keywords and sessions) were arranged in a two-dimensional graph using multi-dimensional scaling (MDS) of geodesic distances between nodes [en nodes  and ploten nodes .In total, 102 individuals from 40 institutions  participated in the Un-Meeting. A third of participants came from within a 100-mile radius of the Un-Meeting location, the remainder represented 16 states and the District of Columbia.The goal of this analysis was to visualize the conceptual distance between and within breakout sessions. Such a mapping can show the conceptual diversity of the conference, grouping of words within the breakout sessions, provide an unsupervised clustering window into the breadth or focus of a particular breakout, and cross-connections between breakouts.1). Unsupervised clustering of the 248 keywords in 150 sticky note ideas resulted in 18 clusters , Criminal Justice (Session 2), Clinical trials (Session 3), Community Engagement (Session 8), Special Populations (Session 11), and Health Insurance/Policy (Session 23). Most sessions addressed systemic and cross-disciplinary issues, involving community, governmental, and policy sectors.We next examined the linkage between breakout sessions and keyword clusters. Breakout sessions also varied in terms of the breadth of the distribution of their keywords across clusters. Six sessions with highest between-cluster breadth shared keywords with five or six clusters. They included Most interestingly, we found that the content of breakout sessions rarely corresponded with keyword clusters, as the content of clusters usually referred to multiple breakout sessions. Thus, clusters related to general medical aspects of addiction and systemic and organizational themes distributed across breakout sessions. Themes related to special populations and disparities did not appear in many sessions and were more specific to the sessions corresponding to these topics.We next analyzed the relationship between keywords and sessions, based on their distribution in a network map, aiming to identify meaningful regions and distinct communities. Figure ‘community engagement’ , ‘technologies and innovations’ , ‘treatments and medications’ , ‘clinical and best practice’ , ‘prevention and education’ , ‘special populations and disparities’ , and ‘system/context/complexity’ .After reviewing, the common features of keyword clustered in different regions of the map and sessions that they bridged. We labeled seven main regions, denoted by the large blue labels in Fig. In summary, we identified thematic regions in the map that can indicate to potential/invisible communities among researchers with common interests and approaches in opioid research. The main clusters included clinical research, translational research using technologies, population health, community engagement, special populations and disparities, and systemic and structural approaches to opioid disorders.In this report, we describe the use of unsupervised clustering based on semantic analysis of concepts and keywords to identify bridging concepts across expert domains and hidden communities of interest within an Un-Meeting involving investigators and research users interested addressing the opioid crisis. We used two complementary approaches to identify clusters of keywords and illustrated the overlap between sessions and keyword clusters, and areas that bridged across potential communities of research. We found that keywords related to treatment, pain, medication, access, and communities span across many breakout sessions that represented focused areas of investigation, while important concepts such as disparity, discrimination/racism, and policy were less frequent and were limited to few focused communities. The network analysis showed that focused communities were bridged by topics pertaining to the complexities of the opioid crisis, including systems, contexts, and community engagement, on one hand, and technologies, innovations, and treatment advancements on the other hand. These bridging concepts represent translational opportunities in opioid research that connect disciplines and research groups.Results of the thematic analysis confirmed the conceptual diversity, with a majority of breakout sessions related to more than one topic area/disciplinary field, and spanning socio-political, technological, and clinical disciplines. This supports the translational nature of opioid research, similar to many other complex fields, in which, the expertise and research focus could not be easily classified by traditional departmental and disciplinary boundaries . This unpreclinical, clinical research, community engagement, computational science and data informatics, and workforce development and implementation science [The opioid crisis affects several aspects of healthcare systems, spanning from prevention and public health to emergency care, and from primary care to specialties. The opioid crisis is even more complicated by a gradual change in the demographics of those most affected, and emergence of new behavioral trends ,32. Thes science . While iCollaboration between clinical and basic sciences researchers to develop new medications and treatments. This is a dominant area in the center of Fig. Community engagement region in Fig. Collaboration between health researchers and community members as well as community-based institutions, to engage stakeholders in research and to address disparities. The System/Context/Complexity in Fig. Special populations/Disparities, which underscores the role of systemic approaches to improve health equity in this area.Collaboration between clinical researchers, system scientists, dissemination & implementation scientists, and sociologists to study the complexities of social systems and organization of care. The region labeled Inspection of the bridging concepts in the keyword-to-session map provides clues for translational opportunities in opioid research to be fostered by CTSA programs. These opportunities include:While the results of our study at a minimum provide a potential roadmap of opportunities for translational advancement in opioid research among this core subgroup of scientists, there are several limitations to be acknowledged. The keywords used in the mapping are based on limited content provided on sticky notes and might miss the complexities and breadth of subject matters to which they correspond. This may affect the richness of conceptual clusters and resulting interpretations. The assignment of topics to breakout sessions was moderated by a facilitator and hence does not reflect a completely unsupervised process of clustering. The topics also reflect the areas of expertise of this particular group of attendees and may not be generalizable. Nevertheless, this method of semantic analysis with thematic network analysis and keyword clustering may be useful for analyzing Un-Meetings with the aim of identifying hidden communities, areas of potential collaboration, and potential gaps in a research network’s ability to impact a chosen translational research problem. The value of these clustering techniques in identifying emerging communities and future collaboration potentials could be assessed using mixed methods studies to incorporate the perspectives and reflections of investigators involved in idea generation activities into the analysis.Our case study of mapping the generated ideas in an Un-Meeting on the opioid crisis, an inherently translational issue, provided insights on the thematic clusters and topic areas that bridge across them. Our findings add to the scientific body of literature on using thematic mapping to reveal the complexities of inter-disciplinary research  and provThe cross-disciplinary nature of topic areas that bridge across thematic communities provide opportunities for CTSA programs to engage and support diverse communities of researchers and users to develop translational teams. Potential opportunities to support translational collaborations include technological advancements of opioid prevention, treatment, and surveillance; studying systems, contexts, and complexities of the opioid crisis, and studies focusing on special populations and health disparities.


In vitro-in vivo discordance in the activity of β-lactams against MBL-producing Enterobacterales has been described. This discordance is likely attributed to the supra-physiologic zinc level in the in vitro testing media, which facilitates the bicyclic β-lactam ring hydrolysis. In this study, we compared the outcome of empirical non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam plus aztreonam) among patients with bloodstream infections due to NDM-producing Klebsiella pneumoniae. Validation of the efficacy of carbapenem in a murine septicemia model was conducted. In vitro susceptibility testing conditions were altered to better predict the in vivo outcome.A retrospective observational study of patients admitted to hospitals in Italy. The primary outcome was 14-day all-cause mortality. Cox regression analysis was performed to evaluate primary outcome. Kaplan Meier survival and log-rank test were used to compare 14-day mortality between patient’s cohorts. Septicemia was induced in mice via intraperitoneal inoculation with the isolates retrieved from the patients then clinical exposure of meropenem  was given for 2 days. Survival was recorded for 4 days and compared with sham controls. Unbound zinc levels were measured in human and infected mice plasma. MEM MICs were determined in Mueller Hinton Broth (MHB) and MHB adjusted to the physiologic zinc levels.Of the patients identified, 29 received empirical non-MBL-active β-lactams for median duration 4 days while 29 received MBL-active β-lactams. The 14-day mortality rate was 21% in the non-MBL-active group vs 14% in the MBL-active group (P = 0.73) and survival patterns were not significantly different . Cox regression showed that use of non-MBL-active therapy was not associated with significantly increased 14-day mortality . MEM treatment resulted in protection from mortality in mice . MEM MICs in zinc-adjusted MHB were 1- to > 16-fold lowered relative to MICs in MHB ( ≥ 64 mg/L).Our data provide foundational support to help establish PK/PD relationships using MICs derived in physiologic zinc levels which may better predict β-lactam therapy outcome.Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support Christian M. Gill, PharmD, Everest Medicines, Shionogi, Cepheid: Grant/Research Support Matthew Gethers, PhD, Thermo Fisher: Employee Marco Falcone, MD, PhD, GILEAD: Grant/Research Support|GSK: Honoraria|MENARINI: Advisor/Consultant|MENARINI: Grant/Research Support|MSD: Honoraria|PFIZER: Honoraria|SHIONOGI: Grant/Research Support Francesco Menichetti, n/a, Aneglini: Advisor/Consultant|Aneglini: Board Member|Aneglini: Grant/Research Support|Aneglini: Honoraria|Astellas: Advisor/Consultant|Astellas: Honoraria|Becton: Advisor/Consultant|Becton: Honoraria|bioMérieux: Advisor/Consultant|bioMérieux: Honoraria|Biotest: Advisor/Consultant|Biotest: Board Member|Biotest: Honoraria|Bristol-Myers Squibb: Advisor/Consultant|Bristol-Myers Squibb: Honoraria|Correvio: Advisor/Consultant|Correvio: Speaker honoraria|Dickinson: Advisor/Consultant|Dickinson: Honoraria|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Honoraria|MSD: Advisor/Consultant|MSD: Speaker honoraria|Nordic pharma: Board Member|Nordic pharma: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria David P. Nicolau, PharmD, Shionogi: Grant/Research Support.


Aim: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder that is characterized by aggressive and dysbalanced wound healing. IPF is mainly a disease of the elderly and thus is likely to share common pathophysiologic mechanisms with other more age-related diseases. Emerging evidence has linked disturbance of sirtuin-1 (SIRT1) expression and activity with aging and diseases of the elderly. In the present study, we aimed to evaluate SIRT1 expression in the peripheral blood mononuclear cells (PBMCs) of patients with IPF given the lack of studies in the literature.Methods: We enrolled 34 IPF patients and 22 healthy volunteers (age and sex-matched). In both groups, SIRT1 levels were assessed in plasma, cell pellets of PBMCs, and supernatant from PBMCs’ culture with and without the addition of 10% human serum. We also measured transforming growth factor β1 (TGF-β1) concentration in plasma from IPF patients and controls.Results: The mean (SD) age (years) of the healthy volunteers was 68.57±6.97 and of the IPF patients was 71.28±5.39 years (p>0.05). The mean SIRT1 concentration was found significantly decreased in the supernatant of PBMCs culture (without the addition of serum) in IPF subjects versus controls . No significant differences were observed between the two groups in the SIRT1 concentration of all the other materials. TGFβ1 concentration of IPF subjects was significantly increased when compared to controls . Decreased SIRT1 levels in no-serum supernatant were predictive of IPF, after adjustment for age and sex .Conclusion: The findings of decreased concentration of SIRT1 in PBMCs supernatant and increased concentration of TGFβ1 in plasma in IPF patients versus controls provide important insights into the role of SIRT1 in IPF and could serve as a tool for the diagnosis and evaluation of patients with IPF. Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults and limited to the lungs, which is associated with poor prognosis . Two-thiIt has been proposed that IPF shares common pathophysiological mechanisms with other age-related disorders like chronic obstructive pulmonary disease and cancer . EmerginBased on the latter observations, we hypothesize that patients with IPF may present abnormal SIRT1 levels and expression compared to controls, and we sought to assess SIRT1 levels in plasma, peripheral blood mononuclear cells (PBMCs), and PBMC culture supernatants in IPF patients and controls. Additionally, we aimed to examine the possible association of SIRT1 with a known mediator of lung fibrosis, TGFβ1.Study populationThirty-four IPF patients and 22 healthy volunteers participated in the study. The inclusion criteria for healthy controls were: age >60 years, a history of no smoking, or any respiratory disorder. Healthy volunteers were age and sex-matched with the patient group. IPF was diagnosed according to international guidelines . The patWhole blood processing and PBMCs isolationTwenty milliliters of whole blood from a peripheral vein of all the participants were collected in tubes with EDTA and processed within three to five hours for the isolation of PBMCs. Then, 10 ml of blood was then diluted with 20 ml of sterile PBS for the isolation of PBMCs as detailed below.Twenty milliliters of Ficoll in a 50 ml Falcon tube were overlaid with the diluted blood by gently pipetting along the wall of the tube. The tube was then centrifuged at room temperature at 2500 rpms with no brakes for 20 minutes, which resulted in the formation of (1) plasma fraction, (2) buffy coat layer, (3) Ficoll-PBS interface, and (4) red blood cell pellet. The plasma fraction was collected with a 1 ml micropipette and stored at −800 °C. The buffy coat was collected with a fresh pipette tip of up to 5 ml volume and directly diluted into 20 ml of sterile PBS in a fresh 50 ml falcon tube. The diluted buffy coat fraction was subjected to a further two rounds of centrifugation at 2500 rpms with no brakes for seven minutes with the removal of the PBS supernatant. The resulting PBMC pellet was disrupted into a cell suspension with 1 ml of RPMI-1640 with no serum or antibiotic additives.PBMCs cultureThe PBMC solution was subjected to cell culture in non-adherent, sterile 12-well plates. Briefly, 0.25 ml of the PBMC suspension was added to either 1 ml of 10% human serum RPMI-1640 or to 1 ml of RPMI-1640 with no serum. The plate was incubated for 48 hours in a humified CO2 chamber. The cell suspension was then subjected to centrifugation at 5000 rpm for five minutes and further divided into pellet and culture supernatant fractions. These fractions were stored at −800 °C until further analysis for SIRT-1(ab171573) or TGF- b1(ab100647) by ELISA. The pellets were subjected to complete lysis prior to ELISA as recommended by the manufacturer's instructions.TGFβ1 and SIRT1 measurementPlasma and PBMC lysates were subjected to SIRT1 (ab171573) and (TGF)-b1 (ab100647) as recommended by the manufacturer’s protocol . Briefly, capture antibody-coated wells were calibrated at room temperature prior to use. Diluted plasma (50 ml) or cell lysate (50 ml) was applied in duplicate wells, followed by the addition of detection antibody against specified antigens, and incubated in a 37 °C humidified incubator for one hour. The samples were then removed from the wells by inversion and each well was washed 3× with wash buffer (350 ml). Each well was treated and received TMB chromogenic substrate (100 ml) followed by a 10-minute incubation in the dark. The color development was then terminated by the addition of the stop solution. The plate was then read for endpoint O.D. using a spectrophotometer at 450 nm. Concentrations of SIRT1 and (TGF)-b1 were then calculated after plotting the standard curves.Statistical analysisData were presented as mean ± SD unless otherwise indicated. The normal distribution was assessed by the Kolmogorov-Smirnov test. Univariate correlations were performed by Pearson’s correlation coefficient or by Spearman’s correlation coefficient according to variable distribution. Comparison between patients and controls was performed with the use of the Student’s t-test or Mann-Whitney U-test according to variable distribution. The values were statistically analyzed with an independent Student’s t-test or one-way ANOVA (for inter-group comparisons). To assess the prognostic value of SIRT1, we used multiple logistic regression analysis. GraphPad Prism software version 8.0  and SPSS 16 statistical package  were used for graphing and statistical analyses, respectively. A p-value of <0.05 was considered to be statistically significant.The baseline characteristics of the study participants are shown in Table The plasma SIRT1 concentration (mean±SD) in IPF was 4.74±5.20 versus 5.48±7.76 ng/ml in healthy volunteers (p>0.05). IPF patients exhibited increased TGF-β1 concentration versus healthy volunteers . Next, we evaluated SIRT1 levels in PBMCs after their lysis. SIRT1 concentration in IPF was 75.5±9.28 ng/ml versus 80.34±16.49 ng/ml in controls without statistically important difference between the samples , and we did not find a statistically important difference between the two groups . In both groups, we observed a statistically important difference in SIRT1 levels between all the isolates (p<0.001). In one-by-one comparisons, all the samples differed significantly, except for the comparison between SIRT1 concentration in plasma and in "no serum" supernatant. SIRT1 concentration was higher in PBMC lysates and was decreased in descending order in the "serum" supernatant, plasma, and finally the "no serum" supernatant, respectively Table .Finally, after adjusting for age and gender, increasing age was associated with an increased likelihood of exhibiting IPF , whereas increased SIRT1 in "no serum supernatant" levels was associated with a reduction in the likelihood of IPF   and in descending order in serum [ΚΚ1] supernatant, plasma, and no serum supernatant in both groups. Interestingly, IPF participants did not exhibit an important difference in SIRT1 concentration between PBMCs and the supernatant of PBMC culture in serum conditions. This is a finding that is suggestive of a stress condition for the PBMCs. The presence or absence of serum during cell culture plays an important role in SIRT1 production from PBMCs. As our findings demonstrate, the absence of serum during PBMCs’ culture results in a statistically important difference in SIRT1 concentration between PBMCs’ lysates and no serum supernatant but not between PBMCs’ lysates and serum supernatant. Furthermore, this difference between the healthy and IPF groups shows an increase in SIRT1 secretion from PBMCs and therefore a possible PBMCs’ disability to retain SIRT1 in the intracellular space. Another possible explanation of these results is a mutation in SIRT1 among the IPF group in a way that causes enhanced SIRT1 protein secretion during PBMC stress.Our study has several strengths and limitations. We used a rather small cohort of IPF patients. However, one has to take into account that IPF represents a rare interstitial lung disease with an annual incidence of 10 per 100,000 people . AdditioIdiopathic pulmonary fibrosis is a fatal age-related disease with an unknown etiology and without any effective medical treatment available. Most patients experience a respiratory decline with resulting respiratory failure and death within two to three years of diagnosis, and the incidence of IPF continues to rise. Consequently, it is important to investigate molecules with a possible role in IPF. We compared the concentration of SIRT1 in plasma, PBMC pellets, and supernatant of PBMCs after their culture in media with and without the addition of human serum. We found significantly reduced SIRT1 in the supernatant of PBMCs of IPF patients in comparison with the healthy group, while a lower concentration of SIRT1 in "no serum" supernatant was predictive of IPF. We also evaluated TGF-β1 concentration in plasma and we found it higher in the IPF group. Our findings support the possible implication of SIRT in IPF pathogenesis and/or diagnosis. The aforementioned observations need further confirmation with future studies.


Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label” indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future. Sarcoidosis is a systemic inflammatory disease of unknown etiology characterized by the presence of non-caseating granulomas in affected organs . The lunNone of the drugs currently used for sarcoidosis treatment have been rigorously studied in large randomized controlled trials (RCTs) , 17. MosThe recently published European Respiratory Society (ERS) clinical practice guidelines help to address these concerns by outlining tentative treatment approaches for various organ manifestations of sarcoidosis . Very imCurrent advancements in personalized and precision medicine as well as the introduction of compounds developed specifically for sarcoidosis treatment, underscore the imperative of standardized elements of clinical trial design in either collective or organ-specific sarcoidosis. Medications used in sarcoidosis warrant rigorous, methodical studies targeted to the patients for whom their use is intended. Nearly 50% of patients requiring therapy for severe forms of sarcoidosis may experience a therapeutic failure  , making This manuscript will review the current and anticipated drug trials in sarcoidosis with a focus on studies evaluating novel molecules and novel therapeutic pathways. Trials advocating for a “hit hard and early approach”  and re-eThe treatment of sarcoidosis is not clear cut and demands rigorous ongoing attention. As noted above, the ERS guidelines reaffirmed two major reasons to initiate treatment . UnfortuAlthough the guidelines and a previously published consensus study advocate for early introduction of steroid-sparing agents, there is no definition of how “early” these can be added , 7. TherCorticosteroids have historically been the prototypical treatment in sarcoidosis, yet they are associated with a reduced HRQoL and significantly high morbidity and organ-threatening toxicities that are dependent on dose, duration and in some cases, genetic make-up –37. PatiThe ERS guidelines and a recently published Delphi consensus statement from a large group of worldwide sarcoidosis experts advocate an approach to therapy that balances the use of reduced doses of corticosteroids with the (early) stepwise addition of steroid sparing anti-inflammatory non-biologic and biologic agents , 7.The proposed approach to corticosteroid use is to limit continuation to a 3–6 month period to allow for demonstration of therapeutic response . During For patients with symptomatic pulmonary sarcoidosis believed to be at higher risk of future mortality or permanent disability from sarcoidosis who have been treated with glucocorticoids or other IST and have continued disease, the guidelines suggest the addition of infliximab to improve and/or preserve lung function and HRQoL . This waThe main focus of this paper is the implementation and investigation of pharmacologic systemic anti-inflammatory therapy, yet it must be noted that there are various non-systemic and non-pharmacologic therapies that have shown benefit in palliating symptoms. The intended use of systemic anti-inflammatory therapy is to halt or reverse active or partially active sarcoidosis along with remission of associated symptoms and physical impairment. Symptoms and physical impairment arising solely from irreversible tissue damage resulting from previously active disease is usually not amenable to anti-inflammatory treatment. Innumerable combinations of both pharmacological and non-pharmacological palliative measures exist to augment HRQoL by ameliorating organ-specific symptoms and physical impairment related to irreversible tissue damage . These iSystemic medications offer hope for reversing the progression of moderate to severe disease activity and if successful provide the opportunity to re-gain global function as close to a person’s baseline as possible. As stated above, the systemic treatment armamentarium in sarcoidosis is limited, while the likelihood of treatment failure is reported to be fairly high . It is cCommonly, treatment failure is interpreted as a drug being unsuccessful in inducing disease resolution or eliciting disease control. While this is true, there are other causes and, additionally, varying shades of lack of therapeutic responsiveness which must be recognized in order to preserve the use of an effective or partially effective drug. Firstly, an absolute lack of treatment responsiveness must prompt consideration of either wrong diagnosis, inactive sarcoidosis with high damage burden or medication non-adherence (requiring exploration through SDM). If active sarcoidosis is confirmed, there may be genetic influences on bioavailability of a particular medication that require attention , 78. ParTolerability is another cause of “treatment failure” and may have the greatest potential for salvaging efficacious systemic medication. Ongoing query into patient perceptions of side effects, as can be accomplished with patient self-reported measures, may support earlier interventions that effect tolerability. Being clinically inquisitive in gaining knowledge in the many strands of administration  and palliation  to enhance tolerability, is pivotal (in the context of SDM) to preserving systemic medication use.Toxicity accounts for another type of “treatment failure.” This area requires dedicated knowledge to preventing and monitoring for toxic medication effects, as well as an opportunity to re-challenge. Often, once an unanticipated toxicity occurs, a person’s confidence in that medication is shaken.Finally, it is important to note that none of the drugs used in sarcoidosis are “curative” and that relapses occur frequently with treatment interruption, medication holidays or with medication tapers. These relapses should not be interpreted as treatment failure but rather as disease recurrence following early discontinuation of treatment. In cases where a relapse occurs after at first a response was achieved, previously successful therapy should be re-instituted, and a more prolonged treatment course considered .For patients who develop new or worsening symptoms while on therapy, it is critical to consider and evaluate for other causes of these symptoms rather than routinely attributing worsening to failed therapy or to established progressive pulmonary or other organ sarcoidosis manifestation , 81. ComCareful definition of the target cohort, as much as is possible, is critical in clinical trial design. Lack of attention to patient selection and cohort enrichment could generate data that significantly under-represent the efficacy of a good drug. A central premise of selection is establishing active sarcoidosis in the target organ(s) that will be sufficiently responsive to an efficacious treatment. This is accomplished in either or both of two major ways: (a) demonstration of inflammation consistent with sarcoidosis to the exclusion of other causes, which may be accomplished by positron emission tomography (PET)/computerized tomography (CT) scan in non-neurosarcoidosis, cardiac PET/cardiac magnetic resonance imaging (cMRI) in CS or brain MRI changes suggestive of edema/inflammation in neurosarcoidosis –102; (b)Additional challenges with patient recruitment include the need to promote diversity and ensure equitable enrollment of minorities and non-white participants. As much as is possible, trial populations should be reflective of the populations affected by the disease of interest. Sarcoidosis occurs three times more commonly in African Americans and presents with disproportionate severity in patients of a lower socioeconomic status (SES) , 104, yeStudies focused on non-pulmonary manifestations of sarcoidosis face the unique challenge that very few patients (< 2% in one large cohort)  will havBesides RCTs, the use of large global registries with well phenotyped patients is also a critical step to systematically study various forms of high-risk or severe manifestations of sarcoidosis and their optimal treatment regimens. Sarcoidosis is a rare disease with heterogenous manifestations, and a potential marginal benefit of registries compared with RCTs is the ability to include a more heterogenous (and more representative) sarcoidosis population so as to gain large numbers and gain insight into the use of off-label therapeutics and novel therapeutic approaches for uncommon and severe disease manifestations. Several such registries are currently in existence and may begin to yield some much-needed information in this regard , 123–125Another limitation of drug development in sarcoidosis has to do with identifying validated measures that reflect clinically meaningful response to therapy. Identifying and validating outcome measures is one of the greatest tasks at hand in organ-specific or multi-organ trial design in sarcoidosis. Even when considering a prevalent manifestation such as pulmonary sarcoidosis, the most used measures such as FVC can be flawed in capturing clinically meaningful change ; and mayThe selection of outcome measures is predicated upon which outcomes or endpoints  are deemed important in validating the hypothesis while remaining cognizant of the drug’s mechanism of action and anticipated side effects. For example, in clinical trials targeting lung involvement and measuring changes in physiologic function as primary outcome, FVC, FEV1 or DLCO is often selected while changes in physical function may warrant use of 6-min walk distance and other outcome measures assessing dyspnea, cough or HRQoL may be selected from a variety of PROMs intended to measure each of these as secondary or exploratory outcomes. As much as is possible, outcome measures should be authenticated to demonstrate content validity, reliability, discrimination between similar but different situations , and responsiveness to changes over time that correlate with clinically meaningful change in disease state. Measures are more likely to be successful when they demonstrate high precision, easy interpretability, cost effectiveness, accessibility, and are without undue risk regarding patient safety, comfort, and fatigability. Measures that are easy and logical to complete and that provide immediate real time feedback to patients are also more likely to be accepted.As noted, the ERS guidelines stress the two major reasons for treatment: avoid organ loss or death (danger) and/or improve HRQoL. Unfortunately, none of currently available literature has used these as a specific endpoint. Since mortality from sarcoidosis, death alone as an endpoint has not been a practical primary endpoint, the time to clinical worsening (TTCW) which includes a composite of predefined endpoints such as disease-related hospitalization, death, transplantation, or worsening of 6-min walk or FVC of 5–10% have been used as primary endpoints in trials for SAPH and pulmonary fibrosis , 131. HoImproving HRQoL should be a core outcome of all clinical trials in sarcoidosis . UnfortuAnother endpoint accepted as reasonable is the ability to taper steroid dosage (steroid-sparing) . While rA possibly more efficient and patient-centered strategy in non-neurosarcoidosis might be the use of changing PET/CT values over time. The use of PET/CT is likely to shorten trial length, confer greater precision of change , allow fHierarchical composite endpoints (HCE) whereby multiple relevant outcomes or components ranked in order of clinical importance/relevance and combined into a single ordinal outcome may also be considered. These components would have to be adapted to both the organ of interest and the study drug under investigation and should capture both the most favorable and least desirable aspects of a drug or intervention , 140. FoSubject retention relies on principles of patient safety, comfort, anticipating medication tolerability and cost of participation. This necessitates incorporation of preventive measures and management of toxicities related to steroid-tapering studies. Such measures include protocols to ensure gastric, bone, endocrine and cardiovascular protection as well as measures to address psychiatric and sleep disturbance that follows any available published guidelines for prolonged steroid use. On the other hand, investigator protocols to help manage side effects of study drug that are anticipated to be frequent and decrease study drug tolerability, should be carefully developed with supportive communication aids and patient brochures in the event side effects arise.Patients are the most valuable element in clinical trials, and it is their participation that enables science and treatment development to advance. Most patients are motivated to participate in trials. However, “motivation” to benefit self or others is not enough for a patient to be able to participate in a clinical trial, as participation in clinical trials often requires a level of financial stability and job security that allows compliance with complex trial schedules and prolonged time off work for multiple study visits—sometimes at centers far away from home. Consequently, only patients that can afford the financial and other losses associated with clinical trials are able to participate without the support of financial coverage for expenses and collateral costs of participation , 142. Foirect expenses paid by patients to attend visits  and collateral costs to the patient . A potential third category might be procedural burden which might relate to the complexity and potential discomfort of study procedures. While a fourth category might be probability of benefit which relates to foregoing other available treatment to participate in a placebo trial or a trial of a medication without clinical precedent, or as is common in sarcoidosis to remain on prolonged toxic medications such as prednisone. Participation in clinical trials occurs on top of the usual anticipated annual financial losses for patients and family members related to the disease itself  are now accepted as an important element of successful clinical trial design . InclusiThe sarcoid granuloma is the immunohistopathologic hallmark of sarcoidosis , 96, 155As noted above, the inciting “antigenic” stimulus in sarcoidosis is unknown, however, several studies support that an inhaled infectious, organic, or inorganic antigen acquired from various occupational and environmental exposures such as moldy environments, metalworking, firefighting, agricultural employment, and occupational exposures to insecticides and building supplies is implicated in disease etiology , 164. A via TLR) results in activation of effector proteins (such as caspase-1) and cleavage of inactive forms of interleukin (IL)-1β and IL-18 into their active forms (The inflammatory response in sarcoidosis is initiated by the innate immune system through activation of membrane-bound pattern recognition receptors (mbPRRs) on the surface of antigen presenting cells (macrophages and dendritic cells) at the alveolar epithelial surface . These mve forms , 180. Acve forms , 168. Thve forms , 168.The core of the sarcoid granuloma consists predominantly of activated CD4 + T helper (CD4 + Th) lymphocytes with rare scattered CD8 + T cells and B cells in the periphery . The adaAlveolar CD4 + Th lymphocytes may also differentiate down a Th17/Th17.1 effector pathway under the influence of IL-1, IL-6, and TGF-β , 187–189Failure to clear the inciting antigen and persistence of a dysregulated immune response has been associated with the development of chronic disease and progression to fibrosis in sarcoidosis . ActivatOther immune mechanisms associated with persistence of the sarcoid granuloma and thus of the development of chronic progressive fibrotic disease include activation of the JAK-STAT pathway , 186 andClinicalTrials.gov is a publicly available database of all privately and publicly funded clinical trials conducted around the world. It includes all studies conducted within the 50 states and in over 200 countries including Japan and Europe , drug intervention, and early Phase 1 through Phase 4 trials, as well as excluding trials of devices or behavioral interventions, and studies that have been withdrawn, suspended, or terminated resulted in 69 studies. During manual review of these studies, duplicate entries as well as trials evaluating nutritional supplements, non-granulomatous manifestations of sarcoidosis, and diagnostic, radiologic, and non-drug interventions were excluded. We also excluded trials completed before 2018. Trials evaluating the same molecule for different disease manifestations (such as for pulmonary and CS) or where an early phase trial has been completed and late phase trial initiated were acknowledged as independent studies. Twenty-eight trials were identified. Fourteen of these trials are in pulmonary sarcoidosis, four in SAPH and three in CS. There are only two trials each in cutaneous and multi-organ sarcoidosis and one each in hepatic, CNS sarcoidosis and sarcoidosis affecting the calcium and Vitamin D homeostatic balance  of patients with pulmonary sarcoidosis and have been shown to play a significant role in the immunopathogenesis of the sarcoid granuloma formation  216–219219. IL-1This is a randomized double-blind placebo-controlled phase 2 trial with open label extension (OLE) evaluating the safety and efficacy of anti-GM-CSF antibody (Namilumab) in patients with chronic pulmonary sarcoidosis . ParticiNamilumab is a fully human IgG1 monoclonal antibody that binds with high affinity to GM-CSF and neutralizes its function , 226. ItAutoantibodies to GM-CSF (GM-CSFab) have been identified in patients with autoimmune pulmonary alveolar proteinosis (PAP) where they are known to be highly pathogenic –234. PAPThis is the most advanced ongoing drug trial in pulmonary sarcoidosis. It is a multicenter randomized double-blind placebo-controlled phase 3 study evaluating the safety and efficacy of two IV doses of Efzofitimod (3 and 5 mg/kg) given every 4 weeks to patients with pulmonary sarcoidosis receiving stable doses of oral corticosteroids taken with or without additional immunosuppressant therapy . As withThe exact mechanism of action of Efzofitimod in sarcoidosis is unclear. It is a novel immunomodulator that selectively binds the immunoregulatory receptor Neuropilin-2 (NRP2). Neuropilins (NRP) are multifunctional, single pass transmembrane, non-tyrosine kinase surface receptors expressed on all vertebrates , 241. TwEfzofitimod is a fusion protein comprised of an immunomodulatory histidyl-tRNA synthetase (HisRS) domain fused to a human IgG1 Fc fragment. HisRS is an important pathogenic antigen (Jo-1 antigen) in autoimmune myositis –247 and via a home monitoring application. The primary study objective is to investigate the efficacy and tolerability of methotrexate as first-line therapy in patients with pulmonary sarcoidosis compared to prednisone  vs. medium dose prednisone . Participants in both groups will be followed for evidence of disease relapse at the end of 18-months . The stuIt is to be noted that patients enrolled in both the SARCORT  as well There have been several recently completed early phase trials of novel therapeutic agents in sarcoidosis.This randomized double-blind placebo-controlled phase 1b/2a pilot study evaluated the safety, efficacy, and tolerability of transdermal nicotine (vs. placebo) given as a daily 21 mg patch for 24 weeks in patients with active symptomatic pulmonary sarcoidosis receiving a maximum daily dose of 10 mg prednisone  without any concomitant 2nd or 3rd line therapy , 263.via α7 nicotinic cholinergic receptors (α7nAChR) which signal through the JAK-STAT pathway  for 16 weeks (CLEAR regimen)—to patients with chronic progressive pulmonary sarcoidosis (CPPS) . ParticiThe study enrolled 97 patients  across four sites in the U.S. 49 patients were randomized to receive CLEAR regimen and 48 patients to Placebo. Each patient received 8 weeks of four drugs (or matching placebo) followed by 8 weeks of two drugs (or matching placebo) based on individual tolerance and toxicity profile during the first 8 weeks . The priThe results of this study are in complete contradiction with results of prior studies that provided evidence suggestive of a potential benefit of CLEAR therapy in patients with pulmonary  and cutaRegardless of the reason for the results obtained, it is important to note that they do not reflect on all antibiotic trials in sarcoidosis. A recently concluded non-controlled open label phase 1b study of Azithromycin 250 mg taken once daily for 3-months in 21 patients with pulmonary sarcoidosis presenting with chronic cough found that Azithromycin led to improved cough metrics and HRQoL measures . PatientSeveral other studies have been recently completed in patients with pulmonary sarcoidosis. These studies evaluated the role of Canakinumab  (NCT02888080) ; and RCIRCI is a complex mixture of prolonged-release adrenocorticotropic hormone (ACTH) and other pituitary peptides . It has Friedman et al. also recently published results from a recently concluded small phase 1 proof of concept study evaluating the role of Tofacitinib given as a 5 mg oral pill twice daily for 16-weeks in 5 patients with pulmonary sarcoidosis . They foThis is a small single center phase II study that is planned to enroll 15 patients with steroid refractory pulmonary and extra-pulmonary sarcoidosis randomized to Sarilumab vs. placebo . SarilumAll enrolled patients will receive Sarilumab given as a subcutaneous injection every 2 weeks for 16 weeks and will undergo a forced steroid taper. Patients who successfully taper off steroids by week 16, will be randomized to receive continued SQ injections of Sarilumab vs. placebo for an additional 12-weeks. The primary outcome of interest is flare-free survival of Sarilumab treated patients defined as ability to remain off prednisone and other therapies while on Sarilumab. This study targets patients with steroid refractory (prednisone dose 10–60 mg/day) and multi-organ disease. It has a unique study design that incorporates patients with pulmonary sarcoidosis enriched for presence of non-life-threatening multi-organ disease. In addition to patients with pulmonary sarcoidosis, the target population includes patients with active glucocorticoid-dependent sarcoidosis affecting the lymph nodes, liver, kidneys, spleen, bone, soft tissues, skin, and/or eyes while excluding patients with fibrotic pulmonary sarcoidosis (FPS), CNS sarcoidosis, and CS . FurtherTofacitinib is a JAK1/JAK3 inhibitor that is currently approved for the treatment of Rheumatoid arthritis refractory to conventional DMARD therapy , 300. AnDamsky et al.  recentlyThis study conducted in France is focused on patients with extra-pulmonary multi-organ sarcoidosis . It is aper se  had sarcoidosis with evidence of PPF  in patients with FPS enrolled 16 patients and was underpowered to determine pirfenidone efficacy . In thatPatients with FPS present varied radiographic profiles which may correlate with lung function , 323. InThere are several ongoing interventional drug trials evaluating new molecules and therapeutic treatment approaches in patients with CS.RESOLVE-Heart (NCT05351554) is a randomized double-blind placebo-controlled phase 2a study that is planned to evaluate the safety, efficacy, and tolerability of Namilumab in patients with active CS . It is aMAGiC-ART (NCT04017936) is an open label Phase 2 pilot study evaluating the role of IL-1 blockade in patients with CS , 333. StCHASM CS-RCT (NCT03593759) is a large phase 3 non-inferiority multi-center multi-national RCT designed to evaluate the optimal initial treatment strategy for patients with active CS , 341. NePropionibacterium acnes in sarcoid granulomas of myocardial tissue (P. acnes lipoteichoic acid concentration (ACNEX) at 6 and 12 months will also assessed (J-ACNES (UMIN 000025936) is the Japanese Antibacterial Drug management for CS, an ongoing multicenter open-label RCT designed to investigate the effect of antibiotic treatment in addition to standard corticosteroid therapy in patients with CS . The pril tissue . Newly dl tissue . The pril tissue . The ratassessed . A minimassessed .This is an exciting time for therapeutic trials and trials evaluating new treatment approaches in sarcoidosis. For the first time in over two decades, preliminary guidance for the diagnosis and treatment of sarcoidosis have been published and work has begun on defining a set of core outcome measures that can be uniformly applied in clinical trials , 5, 22. The outlook to improve future drug trials in sarcoidosis should look to:–Enhance and diversify subject recruitment and retention by eliminating all real and perceived barriers to trial participation. This includes an active outreach to underserved and minority communities.–Clearly define target cohorts and optimize mechanisms of ascertaining who has active disease prior to trial enrollment. Concomitant with this is the need to clearly define physiologic and clinical endpoints of disease that are consistent with the pathobiology of sarcoidosis and at the same time meaningful to patients.–Determine a core set of organ-specific HRQoL and patient-centered outcome measures that will enable comparison of trial results across studies and minimize redundancy and waste of resources.–Optimize clinical trial designs to enrich study populations of pulmonary sarcoidosis for other organs of interest without detracting from pulmonary specific endpoints.–Build in protocols that address and manage steroid toxicities for studies whose primary outcome is “steroid-sparing”; while at the same time seeking new and safer endpoints that capture clinical deterioration and lack of response to therapy without incurring significant steroid toxicities.–Prioritize studies evaluating the appropriate management of FPS. There is a high morbidity and mortality associated with FPS, yet this group of patients are routinely excluded from clinical trials. Recent findings of the similarities between fibrosis in sarcoidosis and IPF and increasing availability and efficacy of anti-fibrotic therapy should serve as a catalyst for further attention to this severe disease manifestation. The various phenotypes of FPS need to be elucidated and optimal treatment approach for these patients determined.–Finally, while this manuscript was limited to only pharmacologic intervention, it is to be noted that there have been advancements in non-pharmacological management of sarcoidosis, and these will need to be studied alongside the pharmacologic interventions for a more holistic approach to patient care.Having come this far, the sarcoidosis community needs to maintain an unflinching resolve to ensure that large scale well designed RCTs be performed for all future therapeutic interventions and that each subsequent/updated guideline reflect an improved grade of evidence for guideline recommendations.Over 50% of patients with sarcoidosis require treatment for their disease yet none of the medications currently used for sarcoidosis treatment has been rigorously studied in large RCTs  and evidThere are several ongoing RCTs evaluating new therapeutic molecules, novel therapeutic targets and steroid alternative treatment regimens in sarcoidosis with several yielding positive early phase results .While these ongoing trials and future potential trials face significant challenges, it is important to note that these challenges are not insurmountable, and several potential solutions have been proffered in this manuscript.All authors wrote, edited, reviewed, and contributed key concepts to the manuscript. All authors approved the submitted version.


To face crises like the COVID-19 pandemic, resources such as personal protection equipment (PPE) are needed to reduce the infection rate and protect those in close contact with patients. The increasing demand for those products can, together with pandemic-related disruptions in the global supply chain, induce major local resource scarcities. During the first phase of the COVID-19 pandemic, we witnessed a reflex of ‘our people first’ in many regions. In this paper, however, we show that a cooperative sharing mechanism can substantially improve the ability to face epidemics. We present a stylized model in which communities share their resources such that each can receive them whenever a local epidemic flares up. Our main finding is that cooperative sharing can prevent local resource exhaustion and reduce the total number of infected cases. Crucially, beneficial effects of sharing are found for a large range of possible community sizes and cooperation combinations, not only for small communities being helped by large communities. Furthermore, we show that the success of sharing resources heavily depends on having a sufficiently long delay between the onsets of epidemics in different communities. These results thus urge for the pairing of a global sharing mechanism with measures to slow down the spread of infections from one community to the other. Our work uses a stylized model to convey an important and clear message to a broad public, advocating that cooperative sharing strategies in international resource crises are the most beneficial strategy for all. It stresses essential underlying principles of and contributes to designing a resilient global supply chain mechanism able to deal with future pandemics by design, rather than being subjected to the coincidental and unequal distribution of opportunities per community that we see at present. To keep a pandemic like the one caused by COVID-19 . UnfortuDue to an exponential increase in demand during epidemic waves, local production increases are rarely fast enough to cover the high need . MoreoveThe primary production of medical products comes from global supply chains (GSC). GSCs have been optimized for cost-efficiency and may therefore lack resilience, such as redundant supply lines or large buffers along the chains. For this reason, a major topic of debate is if and how these GSCs should be restructured or replaced ,10,11. AConsequently, due to the resource scarcity threat in the first wave of the COVID-19 pandemic, multiple countries started to stock, confiscate, and prohibit the exportation of PPE ,15 and dInstead, this paper investigates the question of whether implementing a resource-sharing policy among different regions or countries can enhance essential-resource stock resilience. A PPE-sharing policy differs from increasing the overall resilience of GSCs: instead of ensuring the transport lines from producers to each individual consumer region, a sharing policy entails creating flexible transport lines between the consumer regions. For this reason, it may provide a more feasible approach that is effective at suppressing future pandemics. The current research field into epidemic spreading and COVID-19 lacks studies on sharing strategies for sharing this type of resource. However, the effects of vaccine sharing between two populations have already been studied using a classical multi-compartmental susceptible–infected–recovered (SIR)-based model , concludIn this article we will first present the stylized model we created to investigate cooperative resource sharing, followed by a simulation of sharing scenarios between different GDP-sized community combinations. In brief, the model concerns two communities that can be interpreted as countries, regions, or even cities. We modeled their local epidemics and the spread of infections across the communities, in combination with their (unspecified) PPE resources. PPE availability lowers the infection rate by offering protection and therefore enables suppressing the infection spread to some degree. Of interest are the effects of simulating changes in resource-sharing behavior on the capacity of going through the entire epidemic without fully depleting the PPE stock.The specific contribution of this study is thus not the novelty of our modeling techniques, but presenting an important message to a broad public by using a stylized model. Motivated by the non-cooperative strategies observed at present, it has the purpose to understand at a high level the impact of sharing essential resources and which factors should be taken into account to reach a better local situation for all communities involved.Here follows a functional description of the model needed to understand the results. Readers interested in more technical details are referred to the Extended Methods in S will be used to refer to the PPE ‘stock’ from the DSP model, as susceptibles (from the SIR model) are never referred to outside of the appendix.We developed a simplified demand–stock–production (DSP) model to emulate the usage and production of PPE. PPE can be interpreted here as any physical equipment that may help limit disease transmission. To cover the disease dynamics, including the transmission-mitigating effects of PPE, the DSP model is coupled to a classical susceptible–infected–recovered (SIR) model ,22 withoFor the inter-model coupling, the following two assumptions are used: (1) more protective equipment is needed when the amount of infected increases ,9; and  reaches stock depletion. Although this is already a successful sharing example for A, the time difference is still too short for the combined stocks to be restored sufficiently for the second epidemic in B. That being said, we can see that when the time difference between A and B epidemic onsets is increased further, both communities can achieve a low infected ratio (blue state). In the latter case, there was enough time to replenish the stock levels between the consecutive epidemics to save both communities.The size of the time difference (We defined the medium stock category with this maximum stock of B (the community that gets infected secondly) still reaches high infected numbers even diminishes for the lower maximum stock communities when The observation that sufficient time difference increases the chance of having one or both sharing communities reach a low infected ratio also holds for more intermediate maximum stock communities. This becomes apparent from In summary, the most important result for equal maximum stock community sharing is that communities with insufficient stock to weather the epidemic by themselves can, when agreeing on sufficiently low sharing thresholds, pass the epidemic without reaching the maximal infected ratio. Crucially, for these communities, a large-scale epidemic can be averted only for either or both of them when the time difference between epidemic onsets is sufficiently long. This requires a tailored strategy depending on the dynamics of the disease at hand, but always with a strong focus on mitigating disease spread between different regions by, for example, imposing travel restrictions early in epidemic outbreaks.Upon reading the equal maximum stock results, one could start fearing that sharing poses a risk to the second community. However, as we will further show by presenting the unequal maximum stock sharing results, this fear is unjustified for two reasons: (1) for a low- or medium-stock community, sharing never leads to worse results than non-sharing for both equal and unequal maximum stock combinations; and (2) for higher-stock communities there is hardly any risk in unequal sharing-even when the total shared stock turns out to be insufficiently high for both communities, a higher-stock second community can still weather the epidemic with a low infected ratio .B in the figure). This should again stress the importance of implementing measures to sufficiently slow down infection spread between communities, rather than discouraging higher-stock communities from sharing. Furthermore, in Only for very specific low time differences between epidemic onsets, a secondly affected higher-stock community could possibly be worse off, i.e., experience so-called ‘second community disadvantage’  the time differences between these onsets and agreeing on a low sharing threshold.In other aspects however, the epidemic onset ordering does impact sharing outcomes, which is indicated by some asymmetries that can be observed in the phase plots around An interesting illustration of the effects of increasing the time difference between onset in a lower-stock and higher-stock community is shown in By increasing the threshold, the system passes from a state of depleted stock for the first community, via the maximal total infected ratio and a state of second community disadvantage, to both communities reaching low infected ratios. This effect is indeed asymmetric around The results discussed here solely focus on the three stock categories, as we defined before, to ease result interpretation. For more intermediate stock values, we refer to Summarizing, the unequal maximum stock sharing results presented here again stress the positive combined effect of a low sharing threshold and a sufficient time difference between epidemic onsets. Additionally they show (1) that there is no downside from sharing for lower-stock communities and (2) how high-stock communities may substantially improve the overall epidemic resilience for both communities combined without much increased risk for their own population, as long as sufficient measures are implemented to reduce epidemic spread between the communities.We have introduced a stylized PPE production model with a sharing mechanism for communities facing an epidemic. The model convincingly shows that involved PPE stock sharing can greatly improve total and local epidemic resilience for all combinations of maximum stock communities. Crucially, these sharing strategies should be accompanied by disease spread mitigation measures to increase the time between epidemic peaks. This ensures that both communities have access to large quantities of stock when they need it most. First, we saw that completely blocking the circulation of essential supplies can lead to local stock shortages and subsequently epidemic proliferation. Then, we showed that for all realistically possible scenarios , sharing leads to better overall and local epidemic outcomes than non-sharing. Even if a high-stock community would exist, sharing can never lead to a more negative outcome for any cooperating community as long as the epidemic onset time differences are long enough. It is good to additionally realize that investing in the global reduction of infection rates helps to restrict the total viral circulation and the chance of reinfection in each region. Therefore, these investments are beneficial to all and crucial for final pandemic mitigation. The results thus strongly advocate for a willingness to share big stock proportions, with a special focus on accompanying measures to slow down epidemic spread between communities. In this way, pandemics can be fought way more efficiently and successfully for all parties involved with their respective PPE production limitations.We emphasize that the numbers used in the examples are not intended to be realistic and are merely for illustrational purposes. In particular, what time difference would be ‘sufficient’ will depend on the properties of the virus, the modes in which people have contacts with other people, the infrastructure and production capabilities of the PPE, the preventive measures in place, and so on.As mentioned before: increasing the delay between epidemic onset should evidently be a major focus when implementing this sharing mechanism. To achieve this, participating countries must directly focus on, e.g., limiting international travel when a community gets infected. Interestingly, the process of resource sharing itself could then start posing a threat, by increasing the chance of importing infection cases . This con, and PPE production rate P could differ substantially between communities. At the moment, the only characteristic we varied between communities was their maximum stock There are some simplifications in our model, which could possibly be accounted for in further research. For example, the effective reproduction number n communities and r resource types. Lastly, in all its simplicity, our model could serve as a basis for models of higher complexity that more closely resemble real-world scenarios. After fitting the data of manufacturers, resource usage, and epidemic dynamics, optimal sharing strategies could potentially be estimated with some precision for combinations of collaborating communities, depending on the uncertainties involved. A similar work of fitting is done to predict SARS-CoV-2 evolution [Further interesting extensions could be to include more communities and to tailor the DSP model to specific and possibly multiple resource types. When multiple communities are involved, the necessary individual sharing amount to sufficiently help a community in need reduces as the load can be divided over contributing groups. In our model we have seen that two low-stock communities had too little combined stock to save either of them, even when sharing major proportions of stock. But a bigger group of solely low-stock communities could potentially have enough combined stock to successfully avoid high infected ratios. However, one should note that in this more complex scenario, a more complex sharing strategy decision structure also arises. To model the politics of this, game-theoretic approaches could be used ,25. For volution .Overall, we can see that increasing global resilience to future pandemics is a complex problem that requires an interdisciplinary effort. Although myriad extensions could be made to this model, these additions would have unnecessarily distracted the reader from our main aim of communicating to policymakers how cooperation can improve epidemic resilience. The strengths of this model are its simplicity and comprehensibility, conveying a clear message and recommendations.In summary, this work demonstrates how trade barriers for essential healthcare resources can worsen pandemic outcomes, while cooperation between different communities can successfully avoid resource scarcity and prevent high-infected incidences for all parties involved. We used a stylized model encompassing disease spread and a resource supply chain in two communities. If enough measures were taken to slow down infection spread between them, both communities were able to avoid resource exhaustion at any point during their epidemics by cooperative sharing. This shows that collaboration is a viable solution to avoid resource scarcity. This message is similarly true for vaccines, as we have learned during the current COVID-19 pandemic [The model serves as a proof-of-concept that illustrates how sharing protective equipment resources between communities is a crucial step in epidemic mitigation. Although the model is stylized, we believe that its general insights are easy to understand and essential to disseminate to all stakeholders involved. It advocates for involved sharing strategies between all types of communities, showing that with a high willingness to share and a strong focus on slowing international infection spread, total epidemic mitigation outcomes can be improved greatly. It also successfully demonstrates that high GDP countries should not be afraid to offer help to countries that need it, as potential negative effects for their own population can be abolished if the right disease spread mitigation measures are in place. Furthermore, reducing viral circulation globally reduces each region’s chance of reinfection and is thus in the interest of all. By taking these insights into account, we believe that global initiatives can help prevent essential-resource exhaustion during pandemics. Our study thus shows that mutual resource sharing can potentially support all participating communities during their local epidemics and ultimately lead to the collaborative mitigation of a pandemic.


Azadirachta indica). SuperGrainbags® were more effective in maintaining seed moisture at acceptable levels close to pre-storage conditions than LDPE bags. Both seed germination and seedling coleoptile length were significantly greater in hermetic than LDPE bags. Neem had no effect on seed moisture, germination, or coleoptile length. SuperGrainbags® were also more effective in abating seed damage during storage, although inclusion of neem within LDPE bags also had significant damage. Quantification of seed predating insects and diseases suggested that SuperGrainbags® also suppressed Coleopteran pests and blackspot, the latter indicative of Fusarium graminearum. Conversely, where farmers used LDPE bags, neem also had an additional though limited pest suppressive effect. Post-storage treatment scoring by farmers revealed a strong preference for SuperGrainbags® and no preference differences for or against neem. This study demonstrates a process by which farmers can be involved in the participatory co-design and testing of alternative wheat storage options, and stresses the need to develop SuperGrainbag® supply chains so hermetic storage can be made widely available.Smallholder farmers in Bangladesh often use low-density polyethylene (LDPE) bags contained within woven polypropylene bags to store wheat seed during the summer monsoon that precedes winter season planting. High humidity and temperature during this period can encourage increased seed moisture and pests, thereby lowering seed quality. Following a farm household survey conducted to inform trial design, eighty farmers were engaged in an action research process in which they participated in designing and conducting trials comparing traditional and alternative seed storage methods over 30 weeks. Factorial treatments included comparison of hermetic SuperGrainbags® (Premium RZ) against LDPE bags, both with and without the addition of dried neem tree leaves ( •Surveys identified seed storage methods for participatory trial co-design in Bangladesh.•Storage trials were then conducted with 80 wheat farming households.•Hermetically stored seed had greater germination and coleoptile length than LDPE bags.•Neem slightly reduced damage rates for traditionally but not hermetically stored seed.•Both men and women farmers expressed strong preferences for hermetic storage. These are in addition to Lepidopteran pests such as the Angoumois grain moth ) and some ant (Hymenoptera: Formicidae) species  to stored grains (Sitophilus zeamais Motschulsky) and bean weevils  in Bangladesh and Ethiopia, respectively  and the Department of Agricultural Extension (DAE), studies were conducted in Faridpur, Rajbari, and Gopalgonj districts in central Bangladesh. Both BARI and DAE proposed these districts as locations in which wheat is a crop of importance to food security for smallholder farmers, but in which farm households had challenges with wheat seed storage and in which no prior experimental work evaluating wheat seed storage methods had been conducted .Fig. 1Lo2.2n = 28, 22, and 23 in Faridpur, Gopalgonj, and Rajbari districts, respectively) across six villages . Villages were selected by DAE officials as locations in which field-level extension staff had an interest in research and where farmers had requested guidance on improved seed storage management recommendations. Survey respondents were first randomly drawn from a list of farm households supplied by DAE as having had at least a five-year history of growing wheat in these villages. From this initial list, DAE next identified households for survey based on criteria including (a) their willingness to participate in household trials testing alternative seed storage methods, (b) willingness to include their own saved seed in research trials, and (c) households in which male and female household heads both agreed to be surveyed. When the pre-trial surveys were administered, 72 had been the maximum number of farm households (including husbands and wives) in the selected villages that were willing to be surveyed and met the above criteria. Survey respondents thus included both male and female household heads (husbands and wives) who were interviewed separately by trained male and female enumerators, respectively, using a pretested questionnaire in February of 2012.To assist in the design of participatory household seed storage trials, we conducted a survey of 72 farm households  with paired male and female discussion facilitators in each village during March of 2012. In these meetings, a descriptive summary of survey results was presented in the form of pie-charts on posters, after which a facilitated discussion led by researchers aimed to further elucidate men's and women's perceived wheat seed storage problems and interest in potential solutions. During FGDs, farmers were also introduced to the concept of hermetic storage; combined with DAE staff's partial familiarity with hermetic storage, this spurred farmers' and DAE's interest in testing hermetic SuperGrainbags® (Premium RZ), which had recently begun to be promoted for seed storage in Bangladesh. Further interactions with farmers and subsequent presentation of an initial trial protocol draft in each village in April 2012 aided in the finalization and farmers' endorsement of trial design.2.4Following completion of the participatory trial design process, storage trials were initiated using the protocol co-designed with farmers in each of the villages in which farmers had been surveyed . In addiThe first experimental factor ‘neem’ had two levels - with and without neem addition - based on survey data and FGDs that highlighted how farmers sometimes mix dried neem tree leaves with stored seed to reduce pest losses. The second factor ‘storage device’ (two types: low-density polyethylene ‘LDPE’ bag and SuperGrainbags®) represented traditional and alternative storage devices, respectively. Trials were conducted under household conditions, and with the objective of assessing the performance of storage devices and methods under conditions that could be implemented by resource-poor farmers. As farmers were however largely unfamiliar with hermetic storage principles and SuperGrainbags®, all husbands and wives in each household were given a standard and brief training on how to use the experimental storage devices and maintain experimental treatments.https://www.grainpro.com/grainpro-bag-zipper). The size of both the SuperGrainbags® and the LDPE bags was 70 by 40 cm, the former and later with a thickness of 78 ± 10 and 60 ± 10 μm, respectively. Each household participating in the trials therefore had a total of four bags to store seed in their houses.We supplied each farmer with a new LDPE bag, which they contained within a woven polypropylene bag, as a control treatment. Fertilizer bags in Bangladesh are typically prepared using high strength but low density woven polyethylene strips and are used to contain LDPE bags in grain storage; as such, this treatment mimicked this common farmers' practices. The second storage device was the hermetic storage Premium RZ SuperGrainbag®, hereafter reffered to as a SuperGrainbag®, provided by GrainPro Inc.  were subsequently mixed with seed before storage. The quantity of neem applied was chosen by households during FGDs as an average of what they considered to be the requisite ratio for neem leaves to seed stored  both immediately before and after storage. Following recommendations from BARI for on-farm experiments with a large number of replicates and treatments, we retrieved five randomly selected sub-samples of 50 seeds both before and after storage. Seed germination testing was conducted immediately thereafter in BARI's Seed Testing Laboratory in Gazipur. The five sub-samples of 50 seeds from each treatment combination  from each household were first visually examined for signs of fungal presence and damage signified by cracking or evidence of predation. They were then placed evenly on a moistened and a distilled water damped germination paper towel at 8 a.m. and placed in an incubator at 20 °C for eight days. Moisture was maintained by misting with distilled water at 8 a.m., 2 p.m. and 8 p.m. daily. After the eighth day, normally germinated seeds that showed emerged sprouts were distinguished from dead and abnormally germinated seeds and subsequently counted from each of the five sub-sample groups. Sub-sampled data were then averaged to provide a single germination percentage for each treatment from each household replicate. In addition to germination, seed vigor can be a useful parameter for identifying the potential of seed to perform well after storage . Hence, 2.5.2Prior to removing seed from storage devices after storage, four composite samples of seed equal to 500 g were randomly retrieved from storage devices and placed in bowls. Samples were then thoroughly examined following 2.5.3At the conclusion of storage, male and female household heads together extracted seed from storage devices. Following a visual inspection, they were each independently requested to provide a score between 1 and 4 representing their perception of the effectiveness of each treatment option to maintain seed quality, with 1 being poor, and 4 being high, performance.2.6Farm household survey data across villages and districts were analyzed descriptively and presented as percent total in pie-chart form to farmers during FGDs, and in tabular form in this manuscript. Data for different parameters observed in the household storage trials were analyzed using three models. In the first statistical model, before and after storage measurements of seed moisture content, germination, coleoptile length and damaged seed were analyzed using a repeated measures two-factor factorial ANOVA, with the addition or absence of neem as the first within-subjects factor, and storage device type as the second within-subjects factor. The timing of sampling (before or after storage) was considered as the between-subjects factor. Both within- and between-subjects factors were treated as fixed effects, with replicate considered as a random effect. This model permits the examination of two- and three-way interactions that compare the second (with or without neem) and third (SuperGrainbag® or LDPE bag) factor treatment performance to each other, while accounting for any variation observed in the first factor (before and after storage). In the second statistical model, post-storage data for insects and indicators of disease were analyzed using a factorial ANOVA, with neem (with or without), and storage device (LDPE or hermetic), as the first and second factors, respectively. These factors were also considered as fixed, while farmer replicate was again treated as a random effect. Finally, in the third statistical model, farmer's post-storage preference scoring for storage methods was analyzed using a three-factor design/ANOVA, with storage device, neem, and sex of the survey respondents considered as fixed factors, with household replicates as a random factor.X + 1]), where X is the original observation) before they were subjected to ANOVA. If significance was detected at α = 0.05, treatment means were separated by using the Student's-t or Tukey's Honestly Significantly Different (HSD) test for non-interacting and interacting sources of variation, respectively.All analyses were conducted using the restricted maximum likelihood (REML) procedure in JMP  tablets per storage bag, although most indicated that naphthalin was expensive and regularly not available in the market. The remaining households used various types of insecticides  as protection measures. Only 1% of farmers surveyed used rodenticides.During FGDs, farmers expressed that neither they could neither reliably access nor afford synthetic insecticides as an additive to stored wheat seed. For this reason, they expressed an interest in experimenting with neem leaves, which are occasionally used in the study area  as a pot3.2As described in Section 3.2.1P < 0.001) mean increase (2.8%) in moisture across treatments. The inclusion of neem had no effect on seed moisture, though a significant (P < 0.001) three-way interaction was observed, with SuperGrainbags® preventing seed moisture from rising above 10.4%, while seed moisture in LDPE bags exceeded 12.1%. Seed moisture content after storage demonstrated that of the 160 first factor treatment comparisons, 103 of the observations of LDPE storage had moisture contents >12% before storage, while SuperGrainbags® had only 28  decreased across treatments following storage. The percentage of damaged seed conversely significantly (P < 0.001) increased by 1.5% across treatments (P < 0.001) interaction between sampling time and storage device was observed, with SuperGrainbags® maintaining a germination percentage when compared to pre-storage levels. LDPE bags however were associated with significantly reduced germination by 3.7–4.1% lower than pre-storage levels. A nearly significant (P = 0.08) three-way interaction was also observed, with SuperGrainbags® maintaining germination percentage on-par with pre-storage conditions, yet with neem inclusion to LDPE bags tending towards a slight increase. As with germination percentage, significant (P < 0.001) differences between storage devices were found for coleoptile length when comparing pre- and post-storage conditions. Coleoptile lengths measured following SuperGrainbag® storage were not different than pre-storage lengths. Conversely, coleoptile lengths were 5.0–9.5 mm shorter, on average, following storage in LDPE bags, and were significantly different from pre- or post-storage SuperGrainbag® measurements.Both germination percentage and coleoptile length significantly  between sampling time and inclusion of neem. Each two- and three-way interaction that considered sampling time (before or after storage) as a factor affecting seed damage was significant at either P < 0.05 or P < 0.001. While no differences between treatments were found, and damage levels were low (0.3–0.5%) before storage, the addition of neem to SuperGrainbags® maintained these low levels, while SuperGrainbags® without neem had a significantly higher damage rate of 1.4% after storage. Considering the LDPE bag-based treatments, use of neem lowered damage rates from 3.6 to 2.2% compared to LDPE bags alone, though both LDPE treatments (with or without neem) had higher damage than the SuperGrainbag® treatments.There was a significant interaction  ranged from 0 to 6 for the former family and from 0 to 9 for the groupings of Chrysomelid, Tenebrionid and Bostrichid beetles, with a mean density of 0.5 for Curculionidae and the grouping of other beetles  and no differences among treatments. Our household surveys also suggested that insect pest presence was dominated by Coleoptera. The primary family identified was Curculionidae, with species including  beetles .Table 3IP < 0.05) were found for populations comparing with and without neem addition (−1 seed stored) than the former . Similarly, hermetic storage without neem had a highly significant effect (P < 0.001) on reducing weevil density, with 0.15 individuals kg−1 seed stored compared to when LDPE storage without neem . A significant (P < 0.01) interaction was also found when comparing both factors. In a statistical sense, hermetic storage with or without neem were both equally suppressive of Curculionidae populations, although for LDPE storage, neem addition lowered weevil density by 0.41 individuals kg−1 seed stored , Tenebrionid beetles such as red flour beetle (Tribolium castaneum) and darkling beetle (Coleoptera tenebrionidae), and Bostrichid beetles such as auger beetles (Heterobostrychus sp.) and borers beetles (Rhyzopertha dominica) were found. A single lined flat bark beetle Laemophloeus minutus of the superfamily Cucujoidea was also observed. As each of the population density of these species was relatively low on an individual basis, we bulked all non-Curculionidae beetles into a general category for analysis. Neem addition had similar effects as found with Curculionidae with significant (P < 0.01) differences, and population density 0.35 individuals kg−1 seed stored lower than without neem. Hermetic storage had a similar suppressive effect on population density of Coleoptera, with highly (P < 0.001) significant differences between LDPE bags and SuperGrainbags®, the latter nearly eliminating non-weevil beetle populations relative to the former. A mildly significant (P < 0.05) interaction was also found when these factors were compared, mirroring the same pattern as found for Curculionidae.Considering non-Curculionidae species, Chrysomelid beetles such as bean weevil  different when neem was added, though at low levels of one percentage point less when neem was added to storage devices. SuperGrainbags® had a slightly stronger and significant (P < 0.001) effect, with an incidence of blackspot 1.6% less than LDPE bags. Mildly significant (P < 0.05) interactions were observed, with the highest percentage of blackspot (5.1%) in LDPE bags without neem and dropping to 3.5% in LDPE bags with neem, the latter statistically similar to the degree of disease suppression observed with SuperGrainbags® without neem. Neem addition to SuperGrainbags® however had the greatest (2.9%) blackspot suppressive effect.Following storage, we observed blackspots on seeds indicative of attack by fungus of Order Hypocreales family Nectriaceae 3.2.4P < 00.01) preference for SuperGrainbags® compared to LDPE bags for wheat seed storage (data not shown). No differences in preferences were found between men or women, nor for inclusion or exclusion of neem, under any storage device option.After storing seeds in the LDPE bags and SuperGrainbags® for 30 weeks with or without neem, both male and female (husband and wife) household members indicated significantly greater  of replicate samples. The The characteristics of high germination rate and rapid coleoptile expansion is desirable where farmers sow their wheat seed deeply into the soil, or in zero or reduced tillage systems where shoot emergence may be hampered . Our obs4.2.3The results of the current study suggest that both neem addition and/or hermetic storage could be used to reduce densities of Coleopteran pests when storing wheat over the monsoon in the sub-tropics. During storage, insect and disease-causing organisms’ activities release moisture and energy in the form of heat into the spaces between seeds. Moisture therefore builds up faster and to higher levels from insects and other organisms than from grain respiration alone . Our obsFusarium graminearum can cause blackspots and molds can cause mycotoxins and aflatoxins in stored grain (P < 0.001) effect, with lower incidence of blackspot than LDPE bags. Mildly significant (P < 0.05) interactions were observed, with the higher percentage of blackspotted seed found for LDPE bags without neem than for LDPE bags with neem, the latter statistically similar to the degree of disease suppression observed with SuperGrainbags® without neem. Neem addition to SuperGrainbags® however had the greatest blackspot suppressive effect.Insects can also enhance fungal development because they increase moisture and temperature, open the testa for infection, and can supply inoculum. The fungal pathogen ed grain . Our resThe presence of mycotoxins and aflatoxins as reflected by the presence of molds and blackspots in stored grain suggests the need for the development of control measures to avoid potential losses due to molds and fungal and insect attacks . An impo4.2.4P < 00.01) preference for SuperGrainbags® compared to LDPE bags for wheat seed storage. There were however no differences in preferences between men or women farmers, nor for inclusion or exclusion of neem, under any storage device option. These data suggest that farmers consider SuperGrainbags® to be an effective device for wheat seed storage and that the co-design and participatory implementation of trials by farming households can help inform opinions with experience and evidence. Farmers however also expressed concerns about the SuperGrainbag® as they are not produced domestically and are still not widely or commercially available in Bangladesh. The current cost for an imported SuperGrainbag® is around USD 1.9 compared to USD 0.4 for a locally made LDPE bag. Although these costs appear to be miniscule, farmers who have not participated in trials may have an aversion to investing in hermetic storage out of a perception that LDPE bags are sufficient, especially when used in combination with neem and/or insecticides. Such costs are also higher than those reported by At the conclusion of the storage period, when participating farmers were asked about the relative preference of different storage treatments both male and female (husband and wife) household members indicated significantly greater (We suggest that further action research be conducted by extension services to familiarize farmers with the viability of different storage options. Research to identify Bangladeshi farmers’ willingness to pay for SuperGrainbags® could also help to inform commercialization efforts and/or assist in the development of supportive market policy and incentives for farmers to purchase and access hermetic storage options. Finally, our study suggests that in conducting participatory on-farm research trials, it is important to include novel treatments suggested by farmers – such as the inclusion of neem – as a benchmark from which they can compare among their own traditional and alternative options, as also suggested by 5This study aimed to elucidate farmers’ wheat seed storage practices obtained from a household survey, and to use the data collected during surveys to co-design and implement participatory farm household trials with farming households comparing hermetic SuperGrainbags® and LDPE bags storage, both with and without neem. Our results suggest that SuperGrainbags® are more effective in maintaining seed moisture levels close to pre-storage conditions and in increasing germination and coleoptile length than LDPE bags, with no effect of neem. Hence, SuperGrainbags® could potentially lend additional agronomic advantages due to rapid coleoptile expansion that could aid in wheat seedling emergence and establishment, though this hypothesis requires confirmation under field trial conditions.Fusarium graminearum. For these reasons, where farmers are unable to access or afford hermetic storage bags, the indigenous technique of applying dried neem leaves appears to confer some, albeit limited benefits for pest control. Conversely, the comparatively better and more consistent performance of SuperGrainbags® for the range of parameters and higher preference rankings by participating farmers, suggests that agricultural development programs advising wheat farmers on storage techniques in Bangladesh may wish to focus more on making hermetic storage options widely available and affordable. Lastly, this study demonstrated the value of participatory approaches that actively consult and involve farmers in the selection and design of experimental treatments, and the implementation of long-duration storage trials within their own homes. Such participatory approaches can help validate the performance of promising storage options under real-world, and hence highly relevant conditions, while also serving as a pedagogic tool for extension services and farmers alike.SuperGrainbags® were also more effective in reducing insect damage to seed during storage. Inclusion of neem with LDPE bags also had statistically significant damage abatement effects, although at levels lower than those associated with SuperGrainbags® with or without neem. Hermetic storage bags suppressed the primary seed-predating arthropod pest of Coleoptera order with Curculionidae as the most abundant family, and weevils and other families of beetles. Where farmers used LDPE bags, neem inclusion had some additional pest suppressive effect, with similar patterns for damaged seed and the blackspot Conceptualization: TJK, MMU. Methodology: TJK, MEB, MKG. Formal Analysis: TJK, KH. Investigation: TJK, MMU, MEB, MZK. Data curation: KH, MZH, Writing-Original Draft: TJK, JT. Writing – Review & Editing: TJK, KH, MZH, JT. Project Administration: TJK, MMU. Supervision: TJK, MKG, MMU. Funding acquisition: TJK.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.