Plasmids are important carriers of genes involved in virulence, resistance to antibiotics and heavy metals, and metabolism of compounds, among other specialized functions. The process whereby plasmids spread among bacteria through cell-cell contact is called conjugation, or conjugative transfer. In order to limit the spread of antibiotic resistance to pathogens or improve the spread or persistence of beneficial plasmids in biotechnological or agricultural applications, we need to better understand the factors that determine plasmid spread and persistence in diverse environments. This Research Topic collected a wide range of papers concerning plasmid transfer, including the mechanisms and regulation of conjugative transfer, plasmid maintenance and interactions within a host or in the environment, as well as characterization of plasmids carrying virulence and resistance determinants that could potentially impact public health or agriculture.Miyakoshi et al. provided new insights into the early, differential gene expression of RP4, a highly efficient conjugative IncP-1 plasmid in Pseudomonas putida. Following the approach of Althorpe et al.  were strongly induced in the recipient (transconjugant) cells within 10 min of a conjugation event. Conversely, on the 3' end of the transfer strand, the traJIH operon which encodes the relaxase and other auxiliary proteins of the RP4 plasmid, was upregulated in the donor cells. Since the traJ promoter is the earliest to be transferred, the relaxase may be expressed in the donor cell after regeneration of the oriT-flanking region and likely to displace the autogenous repressors around oriT.Several studies published in this Research Topic focused on various aspects of conjugative transfer mechanisms. While conjugation is well understood for a few model plasmids, there are still multiple outstanding questions related to its regulation, efficiency, effects of co-residing plasmids, and the host range of conjugative plasmid transfer. Expression of the conjugative transfer genes is often tightly regulated by plasmid-encoded, as well as chromosomal, transcriptional regulators but detailed kinetics of gene expression in donor vs. recipient cells is not clear. Zygotic induction is the transient activation of plasmid-encoded genes that occurs during the early stages of conjugation. e et al. , they ankorA and korB regulators are well known to impact rates of conjugative transfer . The antibiotic ciprofloxacin is known to repress korA and korB expression, and stimulate plasmid transfer, so perhaps indole could be used to mitigate this effect and decrease horizontal transfer.Regulation of plasmid conjugative transfer is an active area of investigation. For broad host range IncP plasmids, the Rhizobiaceae such as species of Rhizobium and Agrobacterium, plasmid conjugative transfer is often regulated by self-produced quorum sensing signals known as acyl-homoserine lactones (AHLs) .Population density also regulates and affects conjugative transfer. For plasmids of the Gama et al. tested how the interaction between plasmids, both intracellularly and intercellularly, impacted the persistence of a focal plasmid: whether through effects on host fitness, conjugative transfer rate, or rate of loss during cell division. They concluded that there was a hierarchy amongst these interaction parameters. Plasmid interactions affecting host fitness favored plasmid persistence more than those affecting conjugative transfer rate and lastly plasmid loss during cell division. These results together with previous studies  for mutants in donor chromosomal genes that increased conjugative transfer of IncP plasmids. Three mutated genes, a regulator (fmrR) and two genes likely to be involved in iron-sulfur cluster metabolism (sufA and iscA), were identified, leading to the proposal of a regulatory model by which these genes converge their regulatory impact on IncP conjugation genes.Another growing field is the study of regulatory interactions within a cell between plasmid and chromosome and vice versa. For example, the transfer of F-like plasmids is activated by the plasmid-encoded TraJ and chromosomally encoded ArcA proteins Kawano et al. showed that mutation in a gene encoding a stress-inducible small RNA (sRNA) or its promoter, drastically reduced the fitness cost of harboring the broad-host-range resistance plasmid RP4. Strikingly, the chromosomal parI gene, known to be upregulated under stress response, was also upregulated upon entry of the plasmid. They then further showed that mutations that downregulate or disable the production of this anti-sense RNA lowered the fitness cost to the host.In the last two decades, the number of studies that showed how the cost of a plasmid to its bacterial host can be rapidly ameliorated through either chromosomal or plasmid mutations exponentially increased  proteins of other conjugative plasmids to facilitate transfer. Garcillán-Barcia et al. focused on the relaxase MOBQ4 of an understudied group of mobilizable plasmids in enterobacterial clinical isolates. They identified the helper conjugative plasmids responsible for the dissemination of these plasmids and showed that co-resident plasmids from different MOBQ4 subgroups did not negatively or positively affect their respective abilities to be mobilized.Some small plasmids, although not capable of self-transmission, can be mobilized by other conjugative plasmids. These mobilizable plasmids carry minimally an Samperio et al. showed that broad-host-range plasmids can be used to deliver DNA from E. coli to Gram-positive bacteria. Examples were lactobacilli for which transformation with DNA had not been successful so far.Moreover, as shown by one study here, conjugation can be used as a gene delivery tool in various biotechnology applications. Hernández-Beltrán et al.Mathematical models can be very helpful to explain experimental observations and begin to predict the fate of plasmids in microbial communities. For those interested in an overview and some history of mathematical modeling approaches that have been developed over the years to explain and predict plasmid dynamics, we recommend reading Rhodococcus, virulent isolates cause leafy gall or witches' broom diseases on a number of different plants. Virulence was demonstrated to be plasmid encoded, but there has been some controversy about which plasmid genes are involved in disease incidence and by which mechanisms  plasmid. The Ti plasmid is conjugative between agrobacteria, and this is regulated by the plant interaction and a quorum sensing system encoded by the Ti plasmid. In this issue, Barton et al. revealed that in some A. tumefaciens strains, the co-resident megaplasmid  is also conjugative and encodes its own quorum sensing system. The At plasmid exerts a complex synergistic regulatory impact on Ti plasmid conjugation via regulation and shared conjugation gene functions.This Research Topic includes multiple papers on the impact and dissemination of plasmids in bacteria associated with plants. Phytopathogenic bacteria are well known to often carry their virulence functions on conjugal plasmids. In the plant-associated Gram-positive bacterial genus of Bañuelos-Vazsquez et al. showed that the so-called Sym plasmid of Rhizobium etli was transferred to diverse bacterial community members in the developing nodule and that some of these transconjugants consequently gained the ability to drive nitrogen fixation. Some transconjugants gained the intact replicating plasmid, whereas others apparently integrated the Sym plasmid genes into the resident genome. This study suggested significant plasmid-driven complexity for nitrogen fixation capacity in legume-associated communities.Nitrogen fixation genes of the legume-symbionts rhizobia are also plasmid-encoded and these plasmids are conjugatively proficient  were also found to be commonly associated with broad host range conjugative IncP plasmids in microbial communities of lettuce . These plasmids did not carry the antibiotic resistance genes often found on IncP plasmids in communities of wastewater and sludge, where human and animal waste is processed. In contrast, IncP plasmids were not isolated from communities associated with tomato plants even with high mercury levels suggesting that the plant host may play a role in plasmid ecology in these environments. Finally, a previously cryptic class of IncP-type conjugative plasmids called PromA plasmids (for promiscuous A) were captured from Gram-negative soil bacteria (Hydrogenophaga) found in different agricultural soils in Belgium . Multiple PromA plasmids have been shown to lack accessory genes, and thus their functional consequence beyond driving conjugative transfer of other plasmids was unclear  pESI-like plasmid  have recently emerged causing infections in humans , conferring resistance to third generation cephalosporins used to treat salmonellosis in humans. Yang et al. described another type of mosaic plasmid from Salmonella Derby formed by excision of a chromosomally located MDR fragment flanked by IS elements. The excised MDR fragment was then combined with a conjugal plasmid via homologous recombination.Dissemination of antimicrobial resistance genes among both pathogenic and commensal bacteria is often mediated by mobile genetic elements including plasmids. Knowledge of plasmids harboring resistance genes and the extent of transfer in bacterial populations is essential to development of alternatives to combat antimicrobial resistance. This is especially important as new resistance mechanisms to clinically important antimicrobials are emerging in bacteria previously not known to carry those resistance genes. An example of this is highlighted in a review article of transfer mechanisms and associated antimicrobial resistance in blaNDM gene, IncX, IncA/C, IncH and two plasmids of unknown Inc types were described among clinical carbapenem resistant E. coli isolates from China by Zou H. et al.. Fu et al. had a closer look on plasmids of different Inc types carrying a blaCTX−M gene originating from Salmonella Enteritidis from Shanghai: blaCTX−M−55 gene was most commonly found (in 32 of 38 cases) and in several cases flanked by the insertion sequence ISEcp1 and ORF477. Among the rare E. coli isolates with resistance to ampicillin or cephalosporins from wildlife in Guadeloupe , an IncI1 plasmid with blaM−1CTX− belonging to the sequence type ST3 was described in detail . Zhang et al. described a plasmid carrying a resistance gene to the novel phosphonic drug class fosfomycin. Liu et al. reported a conjugative tetracycline resistance plasmid pTS14 that proved to be very stable in the host. The study dealing with colistin resistance plasmids focused on the identity and transferability of plasmids carrying the colistin resistance gene mcr-1. Also included is an article on the analysis of plasmids in Gram-positive bacteria, including virulence and resistance gene-carrying plasmids, in 222 Staphylococcus aureus isolates from retail meat .Several other papers also focused on the analysis of plasmids of different Inc groups responsible for resistance to beta-lactams. Other than the predominant IncF plasmids harboring a Raoultella ornithinolytica from healthy adults  and Klebsiella pneumoniae from a Red Kangaroo  carried MDR IncF type plasmids with antibiotic resistance phenotypes transferable to an E. coli recipient in mating experiments. Another study analyzed 114 completely sequenced E. coli isolates from pigs and farm workers in Vietnam, transferable plasmids carrying ESBL genes and other resistance genes were identified, whereas no direct transmission of the resistance genes between animals and humans was observed . Law et al. showed that wastewater biosolids served as a reservoir of Prom A and IncP-1 antibiotic resistance plasmids that can transfer their resistance genes to pathogens and commensals, and that some of those plasmids can persist in these novel hosts without antibiotic selection. These studies underscore the importance of monitoring antibiotic resistance plasmids in asymptomatic animals and people, as well as in the environment.Two papers in this Research Topic focused on basic characterization of plasmids conferring antimicrobial resistance in the gut microbiota. Both the opportunistic pathogen Vrancianu et al. wrote a comprehensive review on these various chemical and biological approaches that can be used to eliminate mobile genetic elements as carriers of antibiotic resistance genes.A great deal of fundamental research has led to multiple approaches that are aimed at inhibiting plasmid transfer or accelerating plasmid loss from populations of pathogens with antibiotic resistance plasmids. This Research Topic highlights the active and dynamic area of research on plasmid transfer. Plasmids are important in many different contexts and in distinct environments. Their prevalence and transmissibility make them consistent contributors to specialized bacterial phenotypes such as virulence, antibiotic resistance, exotic metabolism and symbiotic functions. However, plasmids are clearly selfish genetic elements that are under natural selection to maintain and propagate themselves in bacterial populations. Their genetic content, however, can have tremendous impacts on the bacterial hosts in which they reside, including the ability of these bacteria to drive beneficial and detrimental interactions with animals, plants, and other host organisms. Further improving our understanding of plasmids and their transfer mechanisms will continue to inform new strategies of bacterial control and offer new avenues for their biotechnological application.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.C-YC and CJ were supported by the U.S. Department of Agriculture, Agricultural Research Service, Food Safety In-House Projects. CF was supported by NIH grant RO1 GM120337 and the Indiana University Faculty Research Support Program (FRSP). ET was partially supported by the National Institute of Allergy and Infectious Diseases at the National Institute of Health (grant number R01 AI084918).Author KK was employed by MBFG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The opinions in this Editorial are those of the author(s) and should not be construed to represent any official USDA or U.S. Government determination or policy. USDA is an equal opportunity provider and employer.


Strategies to Prevent Central Line-Associated Bloodstream Infections in Acute-Care Hospitals published in 2014. This expert guidance document is sponsored by the Society for Healthcare Epidemiology of America (SHEA). It is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America (IDSA), the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.Previously published guidelines provide comprehensive recommendations for detecting and preventing healthcare-associated infections (HAIs). The intent of this document is to highlight practical recommendations in a concise format designed to assist acute-care hospitals in implementing and prioritizing their central line-associated bloodstream infection (CLABSI) prevention efforts. This document updates the Strategies to Prevent Central Line-Associated Bloodstream Infections in Acute-Care Hospitals: 2014 Update, including recommendations that have been added, removed, or altered. Recommendations are categorized as essential practices that should be adopted by all acute-care hospitals  or additional approaches that can be considered for use in locations and/or populations within hospitals when CLABSIs are not controlled after implementation of essential practices . See Table This section lists major changes from the The subclavian vein is considered the preferable site for central venous catheter (CVC) insertion in the intensive care setting to reduce infectious complications. Previously, the primary recommendation was to avoid the femoral vein for access. Although this remains valid, it has been replaced by a positively formulated recommendation regarding the subclavian site.The recommendation to use ultrasound guidance for catheter insertion is backed by better evidence than was available previously; however, the procedure itself may jeopardize the strict observation of sterile technique.The use of chlorhexidine-containing dressings is now considered an “essential practice”; in the past, it was listed under special approaches that should only be employed if CLABSI rates remain high despite the implementation of basic practices.Routine replacement of administration sets not used for blood, blood products, or lipid formulations can be performed at intervals of up to 7 days. Previously, this interval was no longer than 4 days.Antimicrobial ointment for the catheter site, which is geared toward the population of hemodialysis patients, has been moved to “additional practices” given the focus on a specific population.Despite currently being supported by high-level evidence, antiseptic-containing caps remain an “additional practice” because they are not considered superior to the manual disinfection, an essential practice.The importance of infusion teams has been highlighted by listing it under “additional practices” (previously considered unresolved).Sutureless securement of catheters was not discussed in the previous version of this section.Handbook for SHEA-Sponsored Guidelines and Expert Guidance Documents. No guideline or expert guidance document can anticipate all clinical situations, and this document is not meant to be a substitute for individual clinical judgment by qualified professionals.This document was developed following the process outlined in the This document is based on a synthesis of evidence, theoretical rationale, current practices, practical considerations, writing-group consensus, and consideration of potential harm, where applicable. A summary list of recommendations is provided along with their relevant rationales , the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, as well as representation by the Centers for Disease Control and Prevention (CDC).SHEA utilized a consultant medical librarian, who worked with each panel to develop a comprehensive search strategy for PubMed and Embase . Articles’ abstracts were reviewed by panel members in a double-blind fashion using the abstract management software, Covidence , and subsequently reviewed as full text. The Compendium Lead Authors group voted to update the literature findings, and the librarian reran the search to update it to August 2021. Panel members reviewed the abstracts of these articles via Covidence and incorporated relevant references.Recommendations resulting from this literature review process were classified based on the quality of evidence and the balance between desirable and potential for undesirable effects of various interventions  higher on average than for patients without CLABSIIncreased morbidity and mortality; the use of specific types of catheters that are almost exclusively inserted in ICU patients and associated with substantial risk ; and the fact that catheters are frequently placed in emergency circumstances, repeatedly accessed each day, and often needed for extended periods.Intensive care unit (ICU) population: The risk of CLABSI in ICU patients is high. Reasons for this include the frequent insertion of multiple cathetersNon-ICU population: Although the primary focus of attention over the last 20 years has been the ICU setting, most CLABSIs occur in hospital units outside the ICU or in outpatients.Patients at risk for CLABSI in acute-care facilities are those with a CVC in place: intraoperative patients, and oncology patients.Infection prevention and control efforts should include other vulnerable populations such as patients receiving hemodialysis through catheters, peripherally inserted central venous catheters (PICCs), midline catheters, and peripheral arterial catheters also carry a risk of infection.In addition to CVCs, short-term peripheral catheters,Prolonged hospitalization before catheterizationProlonged duration of catheterizationHeavy microbial colonization at insertion siteHeavy microbial colonization of the catheter hubMultilumen cathetersConcurrent cathetersNeutropeniaBody mass index (BMI) >40Prematurity Reduced nurse-to-patient ratio in the ICUParenteral nutritionSubstandard catheter care Transfusion of blood products (in children)Independent risk factors for CLABSI (in at least 2 published studies)Use consistent surveillance methods and definitions to allow comparison to benchmark data.National Healthcare Safety Network (NHSN) Patient Safety Component Manual for information on the appropriate surveillance methodology, including information about blood specimen collection and surveillance definitions of CLABSIs. The relevant chapter of the manual is “Chapter 4: Bloodstream Infection Event .” This may also affect the reliability of public reporting.Recent data suggest that interrater reliability using NHSN definitions is lower than expected. The evidence presented here includes studies that used either CLABSI or CRBSI as an outcome measure and the lesser accuracy of CLABSI may impact the validity of the evidence.The NHSN surveillance definition for CLABSI is different than the clinical definition for catheter-related bloodstream infection (CRBSI). The latter is subject to various factors .Refer to the Healthcare Infection Control Practices Advisory Committee (HICPAC), Centers for Disease Control and Prevention (CDC)Institute for Healthcare Improvement (IHI)Making Health Care SaferAgency for Healthcare Research and Quality, Outcomes and Clinical Trials CommitteeAmerican Pediatric Surgical Association, The Joint CommissionImplementation Guide to Preventing Central Line-Associated Bloodstream InfectionsAPIC, Infusion Nursing Standards of PracticeInfusion Nurses Society, Several governmental, public health, and professional organizations have published evidence-based guidelines and/or implementation aids regarding the prevention of CLABSI including the following:Are not stratified based on the type of catheter .May not be applicable in their entirety for prevention of bloodstream infections with other intravascular devices.The recommendations in this document focus on CVCs unless noted otherwise. These recommendations:An adequately staffed infection prevention and control program responsible for identifying patients who meet the surveillance definition for CLABSI.Infection prevention staff and, preferably, information technology support to collect and calculate catheter days as a denominator when computing rates of CLABSI and patient days to allow calculation of CVC utilization. Catheter days from information systems should be validated against a manual method, with a margin of error no greater than ±5%.Resources to provide appropriate education and training.Adequate laboratory support for timely processing of specimens and reporting of results, as specified by the supervisor of the surveillance program.Facilities undertaking CLABSI interventions should have the following elements in place:Recommendations are categorized as either (1) essential practices that should be adopted by all acute-care hospitals or 2) additional approaches that can be considered in locations and/or populations within hospitals when CLABSIs are not controlled by use of essential practices. Essential practices include recommendations in which the potential to affect CLABSI risk clearly outweighs the potential for undesirable effects. Additional approaches include recommendations in which the intervention is likely to reduce CLABSI risk but there is concern about the risks for undesirable outcomes, recommendations for which the quality of evidence is low, recommendations in which cost-to-benefit ratio may be high, or recommendations in which evidence supports the impact of the intervention in select settings  or for select patient populations. Hospitals can prioritize their efforts by initially focusing on implementation of the prevention strategies listed as essential practices. If CLABSI surveillance or other risk assessments suggest ongoing opportunities for improvement, hospitals should consider adopting some or all of the prevention approaches listed as additional approaches. These can be implemented in specific locations or patient populations or can be implemented hospital-wide, depending on outcome data, risk assessment, and/or local requirements. Each infection prevention recommendation is given a quality of evidence grade Require education and competency assessment of healthcare personnel (HCP) involved in insertion, care, and maintenance of CVCs about CLABSI prevention Include the indications for catheter use, appropriate insertion and maintenance, the risk of CLABSI, and general infection prevention strategies. Periodic retraining with a competency assessment may be of benefit.Ensure that all HCP involved in catheter insertion and maintenance complete an educational program on essential practices to prevent CLABSI before performing these duties.Periodically assess HCP knowledge of and adherence to preventive measures.Require all HCP who insert a CVC to undergo a credentialing process  to ensure their competency before independently inserting a CVC and aseptic technique for accessing and maintaining the CVC thereafter.Re-educate when an institution changes components of the infusion system that requires a change in practice .Use simulation training for proper catheter insertion and maintenance if available.Bathe ICU patients >2 months of age with a chlorhexidine preparation on a daily basis In long-term acute-care hospitals (LTACHs), daily chlorhexidine bathing may also be considered as a preventive measure. One cluster-randomized study found a significant reduction in device-associated bacteremia with CHG bathing in this patient population; however, some of these patients also received methicillin-resistant Staphylococcus aureus (MRSA) decolonization, making it difficult to draw firm conclusions regarding CHG bathing alone. Several studies have suggested benefit among adult hematology-oncology patients; however, a similar reduction was not observed for pediatric patients with similar conditions. Accordingly, potential benefits and risks, such as increases in resistance and cost, need to be carefully considered.The role of chlorhexidine bathing in non-ICU patients remains unclear. Although life-threatening skin injuries from CHG have been reported in very young or very preterm infants, they typically occur in infants with a birthweight <1,000 g who are <7 days postnatal age, and they appear rare in older infants.The safety and efficacy of routine use of chlorhexidine bathing in infants <2 months of postnatal age remains unclear.Widespread use of chlorhexidine may be associated with decreased chlorhexidine susceptibility, although the clinical relevance of this finding is not well defined.In ICU and non-ICU settings, a facility should have a process in place, such as a checklist, to ensure adherence to infection prevention practices at the time of CVC insertion Checklists have been suggested to ensure optimal insertion practices. If used, the documentation should be done by someone other than the inserter.Observation of CVC insertion should be done by a nurse, physician, or other HCP who has received appropriate education (see above) to ensure that aseptic technique is maintained.HCP should be empowered to stop the procedure if breaches in aseptic technique are observed.Ensure and document adherence to aseptic techniquePerform hand hygiene prior to catheter insertion or manipulation Use of gloves does not obviate hand hygiene.Use an alcohol-based waterless product or soap and water.The subclavian site is preferred to reduce infectious complications when the catheter is placed in the ICU setting In the non-ICU setting, the risk of infection between the different sites remains unclear. Importantly, in emergent settings, ensuring life-saving vascular access in the fastest possible way may determine the choice of access site. Tunneled femoral vein catheters, with an exit site outside the diaper area in the mid-thigh, may be safer and provide additional risk reduction.In children and infants, femoral vein catheterization may be considered if upper body sites are contraindicated. The risk and benefit of different insertion sites must be considered on an individual basis with regard to infectious and noninfectious complications. Among others, this applies to patients currently receiving or likely to require hemodialysis in whom the subclavian site is avoided due to risk of stenosis.Controversy exists regarding infectious and noninfectious complications associated with different short-term CVC access sites. However, the majority of CLABSIs due to PICCs occur in non-ICU settings.Do not use peripherally inserted central venous catheters (PICCs) as a strategy to reduce the risk of CLABSI. Risk of infection with PICCs in hospitalized patients approaches that of other CVCs. and versus CVCs, respectively. Randomized controlled trials comparing the risk of bloodstream infections and other complications associated with these devices are needed.Midline catheters are increasingly being used as an alternative to CVCs for short-term vascular access, with some observational studies suggesting lower bloodstream infection risk associated with midline catheters versus PICCsUse an all-inclusive catheter cart or kit A catheter cart or kit that contains all necessary components for aseptic catheter insertion should be available and easily accessible in all units where CVCs are inserted.Use ultrasound guidance for catheter insertion  but the use of ultrasound may lead to a breach in aseptic technique.Ultrasound-guided internal jugular and femoral vein catheterization reduces the risk of noninfectious complications associated with CVC placementIt is unclear whether ultrasound-guided subclavian vein insertion reduces risk of infectious complications.Use maximum sterile barrier precautions during CVC insertion A mask, cap, sterile gown, and sterile gloves are to be worn by all HCP involved in the catheter insertion procedure.The patient is to be covered with a large (“full-body”) sterile drape during catheter insertion.Use maximum sterile barrier precautions:These measures should also be followed when exchanging a catheter over a guidewire.; nevertheless, most available evidence suggests risk reduction with this intervention.A prospective, randomized study in surgical patients showed no additional benefit for maximum sterile barrier precautionsUse an alcoholic chlorhexidine antiseptic for skin preparation The antiseptic solution must be allowed to dry before making the skin puncture.Alcoholic chlorhexidine for skin antisepsis to prevent CLABSI in NICU patients should be used when the benefits are judged to outweigh potential risk.Before catheter insertion, apply an alcoholic chlorhexidine solution containing at least 2% chlorhexidine gluconate to the insertion site.Ensure appropriate nurse-to-patient ratio and limit use of float nurses in ICUs Observational studies suggest that an adequate nurse-to-patient ratio must be maintained in ICUs where nurses are managing patients with CVCs and that the number of float nurses working in the ICU environment should be minimized.Use chlorhexidine-containing dressings for CVCs in patients over 2 months of age It is unclear whether there is additional benefit with use of a chlorhexidine-containing dressing if daily chlorhexidine bathing is already established and vice-versa.For long-term catheters  in well-healed access sites, it is unclear whether use of a chlorhexidine dressing reduces risk of infectious complications.For children under 2 months of age, use of chlorhexidine dressings remains unclear, particularly in very preterm or low birthweight infants.For nontunneled CVCs in adults and children, change transparent dressings and perform site care with a chlorhexidine-based antiseptic at least every 7 days or immediately if the dressing is soiled, loose, or damp. Change gauze dressings every 2 days or earlier if the dressing is soiled, loose, or damp. Less frequent, clinically indicated dressing changes may be used for NICU patients or others at high risk of serious complications from catheter dislodgement.If there is excessive bleeding or drainage from the catheter exit site, use gauze dressings instead of transparent dressings until drainage resolves.Disinfect catheter hubs, needleless connectors, and injection ports before accessing the catheter Before accessing catheter hubs, needleless connectors, or injection ports, vigorously apply mechanical friction with an alcoholic chlorhexidine preparation, or 70% alcohol. Alcoholic chlorhexidine may have additional residual activity compared to alcohol for this purpose and is therefore preferred. It is unclear whether this duration of disinfection can be generalized to needleless connectors not tested in these studies.Apply mechanical friction for a minimum of 5 seconds to reduce contamination.Monitor compliance with hub-connector-port disinfection because approximately half of such catheter components are colonized under conditions of standard practice.Remove nonessential catheters  However, reducing CVC utilization may result in increased use of other intravascular catheters with corresponding infection risk.Assess the need for continued intravascular access on a daily basis during multidisciplinary rounds. Remove catheters not required for patient care. Decreasing CVC utilization reduces CRBSI risk. Both simple and multifaceted interventions are effective at reducing unnecessary CVC use.Audits to determine whether CVCs are routinely removed after their intended use may be helpful.Routine replacement of administration sets not used for blood, blood products, or lipid formulations can be performed at intervals up to 7 days The optimal replacement of intermittently used administration sets is unresolved.Perform surveillance for CLABSI in ICU and non-ICU settings Measure unit-specific incidence of CLABSI  and report the data on a regular basis to the units, physician and nursing leadership, and hospital administrators overseeing the units.Compare CLABSI incidence to historical data for individual units and to national rates .Audit surveillance as necessary to minimize variation in interobserver reliability.Use antiseptic- or antimicrobial-impregnated CVCs Hospital units or patient populations have a CLABSI rate above institutional goals despite compliance with essential CLABSI prevention practices. Some evidence suggests that use of antimicrobial CVCs, along with other preventive technologies, may have no additional benefit in patient care units that have already established a low incidence of catheter infections.Patients have limited venous access and a history of recurrent CLABSI.Patients are at heightened risk of severe sequelae from a CLABSI .The risk of CLABSI is reduced with some currently marketed antiseptic-impregnated  catheters and antimicrobial-impregnated  catheters. Use such catheters under the following conditions:Monitor patients for adverse effects such as anaphylaxis.Many studies investigating antimicrobial-impregnated catheters were performed before infection preventive bundles were routine. Whether such catheters have an impact on CLABSI in such settings remains unknown.Use antimicrobial lock therapy for long-term CVCs Patients with long-term hemodialysis catheters who have a history of recurrent CLABSI.Prophylaxis for patients with limited venous access and a history of recurrent CLABSI.Patients who are at heightened risk of severe sequelae from a CLABSI .Antibiotic and antiseptic locks are created by filling the lumen of the catheter with a supratherapeutic concentration of an antibiotic solution and leaving the solution in place until the catheter hub is re-accessed. Such an approach can reduce the risk of CLABSI. The optimal antimicrobial agent or combination of agents, their concentration, and duration of lock therapy are matters of ongoing research. Due to concerns regarding the potential for the emergence of resistance in exposed organisms, use antimicrobial locks as a preventative strategy for the following: The potential of adverse effects associated with ethanol locks should be carefully considered before use.To minimize systemic toxicity, aspirate rather than flush the antimicrobial lock solution after the dwell time has elapsed.Use recombinant tissue plasminogen activating factor (rt-PA) once weekly after hemodialysis in patients undergoing hemodialysis through a CVC Utilize infusion or vascular access teams for reducing CLABSI rates peripheral intravenous catheters reduces the risk of bloodstream infections; however, few studies have been performed regarding the impact of intravenous therapy teams on CLABSI rates.Studies have shown that an infusion/vascular access team responsible for insertion and maintenance of Use antimicrobial ointments for hemodialysis catheter insertion sites Apply polysporin “triple” (where available) or povidone-iodine ointment to hemodialysis catheter insertion if compatible with the catheter material.Ingredients in ointments may interact with the chemical composition of some catheters. Thus, ensure the selected ointment will not interact with the catheter material before any such product is applied to the catheter insertion/exit site. For example, ointments containing glycol should not be applied to insertion/exit sites of polyurethane catheters.Mupirocin ointment should not be applied to the catheter insertion site due to the risks of facilitating mupirocin resistance and the potential damage to polyurethane catheters.Use an antiseptic-containing hub/connector cap/port protector to cover connectors The utility of routinely disinfecting hub connectors and ports when using antiseptic-containing hub/connector cap/port protectors is unknown.Several additional approaches are currently available for use. Perform a CLABSI risk assessment before considering implementation of any of these approaches, taking potential adverse events and costs into consideration. Although it is reasonable to evaluate the utility of technology-based interventions when CLABSI rates are above the institutional- or unit-based threshold, this is also an opportunity to review practices and consider behavioral changes that may be instituted to reduce CLABSI risk. These additional approaches are recommended for use in locations and/or populations within the hospital with unacceptably high CLABSI rates despite implementation of the essential CLABSI prevention strategies listed above. These measures may not be indicated if institutional goals have been consistently achieved.Do not use antimicrobial prophylaxis for short-term or tunneled catheter insertion or while catheters are in situ Systemic antimicrobial prophylaxis is not recommended.Do not routinely replace CVCs or arterial catheters Routine catheter replacement is not recommended.Routine use of needleless connectors as a CLABSI prevention strategy before an assessment of risks, benefits, and education regarding proper use Clinical evidence is limited regarding the risk reduction with their routine use or use of other antimicrobial catheter connectors.Use of silver-coated catheter connectors may be associated with reduced intraluminal contamination in ex vivo catheters and CLABSI.Multiple devices are currently available but the optimal design for preventing infections is unresolved. The original purpose of needleless connectors was to prevent needlestick injuries during intermittent use. No data are available regarding their use with continuous infusions. Needle-free connectors with 3-way stopcocks may increase the risk of catheter infections.Surveillance of other types of catheters Peripheral arterial catheters, short-term peripheral venous catheters and midline catheters are not included in most surveillance systems although they are associated with risk of bloodstream infection. Future surveillance systems should consider including bloodstream infections associated with these types of catheters.If considering further infection prevention interventions due to concern for an increase in infections, hospitals may want to consider extending their surveillance programs to include all types of catheters used to gauge the size of the problem.Standard, nonantimicrobial transparent dressings and CLABSI riskA meta-analysis reported an association between CLABSI and transparent dressing use; however, the source studies for the meta-analysis reporting this association were of low quality.The impact of using chlorhexidine-based products on bacterial resistance to chlorhexidine However, testing for chlorhexidine susceptibility is not standardized. The clinical impact of reduced chlorhexidine susceptibility is unknown.Widespread use of chlorhexidine-based products  may promote reduced chlorhexidine susceptibility.Sutureless securementThe impact of sutureless securement devices in reducing CLABSI is unknown.Impact of silver zeolite-impregnated umbilical catheters in preterm infants (applicable in countries where it is approved for use in children)One randomized study suggests that antimicrobial-impregnated umbilical catheters appear to be safe and effective in NICU patients.Necessity of mechanical disinfection of a catheter hub, needleless connector, and injection port before accessing the catheter when antiseptic-containing caps are being used.It is unknown whether the application and removal of an antiseptic-containing cap provides the same benefit to reducing risk of CLABSI as manual disinfection. Future research is needed to determine if using such a cap will obviate the need for manual disinfection before accessing a catheter. and do not necessarily address external reporting needs.These performance measures are intended to support internal hospital quality improvement effortsThe process and outcome measures suggested here are derived from published guidelines, other relevant literature, and the opinion of the authors. Report process and outcome measures to senior hospital leadership, nursing leadership, and clinicians who care for patients at risk for CLABSI.Compliance with CVC insertion guidelines as documented on an insertion checklistAssess compliance with the checklist in all hospital settings where CVCs are inserted  and assign HCP familiar with CVCs to this task.Documenting compliance using the insertion checklist upholds accountability and compliance with the proper procedure steps and identifies gaps to be mitigated. The Institute for Healthcare Improvement (IHI) provides an example of a central catheter checklist.Numerator: Number of CVC insertions that have documented the use of all 3 interventions  performed at the time of CVC insertion.Denominator: Number of all CVC insertions.Multiply by 100 so that the measure is expressed as a percentage.Documentation of CVC insertion procedures in compliance with appropriate hand hygiene, use of maximal sterile barrier precautions, and use of chlorhexidine-based cutaneous antisepsis of the insertion site:Compliance with documentation of daily assessment regarding the need for continuing CVC access.Numerator: Number of patients with a CVC who have documentation of daily assessment.Denominator: Number of patients with a CVC.Multiply by 100 so that the measure is expressed as a percentage.Measure the percentage of patients with a CVC where there is documentation of daily assessment:Simulation of catheter maintenance as an alternative to address HCP competencyNumerator: Number of HCP properly simulating the aseptic infusion of medications.Denominator: Number of HCP simulating the aseptic infusion of medications.Multiply by 100 so that the measure is expressed as a percentage. The standardized utilization ratio (SUR) is an NHSN measure that accounts for facility- and location-level factors that may affect device use.SUR: Observed device days divided by predicted device days.Device utilization can be evaluated over time to assess any changes. Utilization may be compared at the hospital and unit level. It provides a surrogate for patient exposure risk.CLABSI rate: Use NHSN definitions.Numerator: Number of CLABSIs in each unit assessed (using NHSN definitions).Denominator: Total number of catheter days in each unit assessed (using NHSN definitions).Multiply by 1,000 so that the measure is expressed as number of CLABSIs per 1,000 catheter days.Risk adjustment: Stratify CLABSI rates by type of patient-care unit.Report comparisons based on historic data and NHSN data, if available.dSIR: Observed CLABSI events divided by predicted CLABSI events based on actual device days.Use the NHSN device standardized infection ratio (dSIR) to evaluate hospital and unit CLABSI rates. accounts for both device SIR and SUR, reflecting both the care of the device, and interventions to reduce utilization.pSIR: Observed CLABSI events divided by predicted CLABSI events based on predicted device days.Consider measures that address device risk at the patient population level. A population SIR (pSIR) Recommendations for public reporting of HAIs have been provided by the Healthcare Infection Control Practices Advisory Committee (HICPAC), the Healthcare-Associated Infection Working Group of the Joint Public Policy Committee, and the National Quality Forum.Many challenges exist in providing useful information to consumers and other stakeholders and in preventing unintended consequences of public reporting of HAIs.Hospitals in states that have mandatory reporting requirements for CLABSI must collect and report the data required by the state.For information on state and federal requirements, contact your state or local health department.Hospitals that participate in external quality initiatives or state programs must collect and report the data required by the initiative or the program.Problems with interrater reliability may affect comparisons between different institutions. to CLABSI prevention, including formal training of HCP on indications, placement, and maintenance of devices, in addition to regular assessment of competencies.Prevention of CLABSI depends on integrating best practices to reduce the risk of infection and incorporating a culture to support implementation. Hospitals should address technical and socioadaptive components), involves summarizing evidence, identifying local barriers to implementation, measuring performance, and ensuring that patients receive the infection prevention intervention by addressing knowledge, critical thinking, behavior and psychomotor skills, as well as attitudes and beliefs of all members of the healthcare team involved with the insertion and care of CVCs. Facilities may consider utilizing tools to promote high-reliability processes  and to enhance teamwork .One example of a widely used model in the United States, known as the Four Es  is planned.A standardized competency assessment checklist should be used to assess and document competency of each individual performing CVC insertion and procedures related to care and maintenance . Multidisciplinary teams should set clear goals and identify the key factors to be measured. It is important for members of the healthcare team to receive feedback on their performance. Feedback should include periodic  communication  of process measurement data via posters, reports, or other forms of communication with graphs showing cumulative compliance with process measures. Differences between age groups should also be considered . Central line data can be used to capture trends over time. The standardized utilization ratio (SUR) provides a method for the hospital’s units to compare themselves to others with similar characteristics. CLABSI events are important to discuss with the different members of the team caring for the patient to have a clear understanding of gaps and ways to mitigate them in the future.Evaluation involves both process and outcome measurement.


This second volume of our Research Topic ties in with the previous one spotlighting most important issues in emergency psychiatry: suicidality, coercive measures and coping of psychological challenges for health care providers.Hennings et al. show that previous SA—which is also an important clinical suicide risk factor—not only have an attenuating effect on the HPA axis activity during a depressive episode but also impact on the recovery of altered HPA axis reactivity due to depression indicating both, acute effects on HPA axis as well as persistent alteration on stress hormone regulation related to a history of suicide attempts.Suicidality is without doubt one of the most alerting and urgent symptomatology in mental health. More than 700,000 people worldwide die by suicide every year, and the number of suicide attempts (SA) is estimated as 20-times higher . While rWang et al. Further stressing the need of effective suicide prevention and in line with a world-wide phenomenon, Li et al. describe in a large dataset of North China that most suicide attempters admitted to hospital were relatively young (15–34 years) in both, urban and rural areas. While pesticide self-poisoning accounts for about one-third of the world's suicides .Chronic pain as well as serious physical conditions associated with somatic disorders like cancer are well known contributors to suicidality , 7. But suicides , it is fsuicides , knowledCzernin et al. now demonstrate that in the same time incidence of forced medication did not increase but that the maximum doses of psychiatric drugs needed for acute symptom control can even be reduced including maximum forced haloperidol dose. These findings support the development of a more participating and recovery-orientated psychiatric care also in acute settings and may improve the public recognition of mental health care provided by psychiatric hospitals and their acceptance of the patients.Despite significant negative impact on mental health including the development of symptoms of PTSD , 11 but Abdulaziz Alghamdi for disaster emergency medicine services including those occupied in terror attacks, earthquake and COVID-19 pandemics, health care providers can significantly suffer from anxiety and affective disorders as well as PTSD symptoms. Indeed, they themselves need professional support in many cases. Modern technologies like app-based programs (Although the emotional distress occurring in health professionals while being confronted to coercive means , as suicprograms , 22 my pJH wrote the first draft of the manuscript. Both authors contributed to manuscript revision, read, and approved the submitted version.


Ongoing climate change is a major threat to biodiversity. As abiotic tolerances and dispersal abilities vary, species-specific responses have the potential to further amplify or ameliorate the ensuing impacts on species assemblages. Here, we investigate the effects of climate change on species distributions across non-marine birds, quantifying its projected impact on species richness (SR) as well as on different aspects of phylogenetic diversity globally. Going beyond previous work, we disentangle the potential impacts of species gains versus losses on assemblage-level phylogenetic diversity under climate change and compare the projected impacts to randomized assemblage changes. We show that beyond its effects on SR, climate change could have profound impacts on assemblage-level phylogenetic diversity and composition, which differ significantly from random changes and among regions. Though marked species losses are most frequent in tropical and subtropical areas in our projections, phylogenetic restructuring of species communities is likely to occur all across the globe. Furthermore, our results indicate that the most severe changes to the phylogenetic diversity of local assemblages are likely to be caused by species range shifts and local species gains rather than range reductions and extinctions. Our findings highlight the importance of considering diverse measures in climate impact assessments. These changes can be assessed through phylogenetic diversity, i.e. the diversity of phylogenetic lineages present in the assemblage . One aspComparing these two metrics of phylogenetic diversity when investigating temporal change in species assemblages can yield valuable information on the underlying compositional changes that are taking place. Though both metrics measure related aspects of phylogenetic diversity, they are mathematically independent and react differently to changes in species assemblages, allowing inference of four potential ways in which the phylogenetic structure of these assemblages could shift when undergoing climate-induced compositional changes as follows: (i) both MPD and Faith PD could decrease, which indicates a pattern of increasing phylogenetic homogenization (e.g. through a loss of species or phylogenetic lineages that were not closely related to remaining lineages); (ii) both MPD and Faith PD could increase, indicating increasing phylogenetic diversification ; (iii) MPD could increase while Faith PD decreases, indicating increasing phylogenetic over-dispersion (e.g. through a loss of closely related species); or (iv) MPD could decrease while Faith PD increases, indicating increasing phylogenetic clustering of the species assemblage (e.g. through a gain of closely related species or evolutionary lineages).Regardless of direction, changes in species richness (SR) (i.e. the gain and loss of species into and from a species assemblage) could result in severe changes to the phylogenetic structure of species assemblages that are different from expectations under phylogenetically random species gain or loss and likely to have strong ecological effects. To date, the phylogenetic signal of species extinctions through climate change has been found to be rather weak across larger scales . HoweveAn additional complication that has been largely ignored in existing projections of future climate change impact is that local phylogenetic diversity will not only be subject to change through species losses but also through species that newly arrive into an area due to shifts in species geographic range boundaries. Disentangling the impacts of species losses and gains, rather than looking at the overall change in phylogenetic diversity, is important to fully assess and understand the projected changes. For example, a given assemblage could decrease significantly in phylogenetic diversity through species loss, but also increase significantly through species immigration, so the overall change in phylogenetic diversity under climate change would be marginal despite a significant change in the underlying phylogenetic structure of the assemblage.Here, we first (i) investigate how projected range shifts and  species extinctions induced by climate change affect the spatial pattern of phylogenetic diversity for an entire taxon, using the world's terrestrial bird species. Second, (ii) we compare how the projected changes in local species assemblages differ from what would be expected at random given the projected local SR change and disentangle non-random changes through local species gain and loss.Faith PD has often been found to be highly correlated to SR for various taxa ,23, with. 2et al. [Preparation of species distribution and climatic data, as well as the format for species distribution models (SDMs) and the design of the chosen dispersal buffer, follow methods described in Hof et al. . Here, w (a)et al. [We used expert range maps for the breeding ranges of 9882 terrestrial bird species from BirdLife International , consideet al. .For the phylogenetic analysis, we compiled a consensus tree based on a full species-level phylogeny of extant birds . We foun (b)change in SR was calculated as the proportional change between the number of species projected to occur in a grid cell currently and in the future. Second, total change in Faith PD was calculated as the proportional change between the Faith PD  and future species assemblages for each grid cell globally based on the projected species distributions. Then, ollowing ) values ollowing ) value o (c)remainingminus Faith PDcurrent, or MPDremainingminus MPDcurrent, respectively (a); changes caused by species gain were calculated as Faith PD(remaining+gain)minus Faith PDremaining, or MPD(remaining+gain)minus MPDremaining, respectively (b). We evaluated whether the projected changes in Faith PD and MPD were different from what could be expected if the species that moved in or out of an area were randomly distributed across the phylogeny. These randomizations constitute a widely accepted null model approach and are necessary because the structure of the phylogeny determines the possible extent of projected changes in Faith PD and MPD given a particular species assemblage and number of species moving in or out [We decomposed the net change in SR in a given assemblage (grid cell) into the species persisting, the species projected to be lost (through extinction or emigration), and the species projected to be gained (through immigration) under climate change . We thenectively a; changeectively b. We evan or out ,34.Figua). To assess the statistical significance of differences between the projected change in the phylogenetic metrics and changes based on random species removals, we calculated a two-sided p-value as the proportion of the 1000 random values that were smaller or larger than the observed value.Random changes through species loss were calculated in both phylogenetic metrics of a species assemblage (grid cell) using the list of species projected to be currently present in the assemblage by the SDMs. The same number of species as projected to be lost from the assemblage was then repeatedly (1000 times) removed from the current species assemblage at random, and both phylogenetic metrics were recalculated each time a. To assb). We extracted the number of species that were projected to be gained by the assemblage (grid cell) and then, using this number, we randomly added new species to those that were projected to remain in the assemblage under climate change, using a species pool based on estimated species’ dispersal abilities. This species pool definition means that our null model for species gain is more biologically defined than the null model for species loss . Again, we calculated a two-sided p-value indicating if there was a significant difference between the projected change in both phylogenetic metrics and changes based on random species being gained by the assemblage.We followed an equivalent approach to assess non-randomness of the change in both phylogenetic metrics based on species projected to be gained by the assemblage . All analyses were performed in R [All data and codes needed to re-run the analysis and create the plots can be found on Dryad  and a different dispersal scenario . (a)a). These SR changes are spatially highly correlated with projected total changes in Faith PD across the globe (b). Although proportional decreases in both SR and Faith PD are likely to be most extreme in species-poor regions (e.g. the Saharan and Arabian deserts), we also project high proportional decreases in some of the species-rich regions of the world, e.g. in parts of South America and on New Guinea . Whereas assemblages with decreases up to 30% in both metrics may be found across all continents, those with a projected proportional gain are especially widespread at high northern latitudes across the Nearctic and Palaearctic realm. The projected total changes in MPD (f) differ substantially from the projected changes in SR (c) and Faith PD, and are often the opposite to these, which is especially apparent in Europe (g–i). The areas with strong increases in SR and PD across the northern Nearctic and Palaearctic are projected to decrease in MPD, whereas assemblages with SR and PD increases in South America and New Guinea are projected to also increase in MPD.The projected changes in SR within assemblages (grid cells) do not differ greatly across continents but do differ within them a. These he globe b. Althouw Guinea d,e. Whers in MPD f differ es in SR c and Fain Europe g–i. The When directly comparing projected changes in the two phylogenetic structure metrics and disregarding the quartile of assemblages with least change along both metrics , we find (b)a, blue areas). These assemblages are projected to lose species through climate change that represent unusually low amounts of evolutionary history, but these species losses apparently do not lead to consistent significant changes in net relatedness of those assemblages . By contrast, areas with a significantly stronger decrease in Faith PD than we would expect at random (through the loss of species), are most common in central South America and southern African regions, but also prevail across parts of North America and northern Asia . The assemblages in these areas are projected to lose species that represent disproportionately high amounts of evolutionary history. They also mostly experience parallel significant decreases in MPD compared to random species loss , indicating significant increases in net relatedness that further highlight the losses of evolutionary unique species we find in Faith PD analyses.When we teased apart whether changes in phylogenetic assemblage structure from species loss versus species gain were statistically significant, we found differences among PD and MPD results in many areas that confirmed the pattern comparison described above. Small areas exist on all continents where the decrease in Faith PD through a projected species loss is significantly less severe than expected from randomized species moving out of the assemblage; these areas are most frequent in the northern Palaearctic and Nearctic . This category of significantly lower increase in Faith PD is the most widespread in extent, indicating that not only are more areas projected to gain more species than lose them (d), but also that the species gains in these areas may not lead to the expected increases in evolutionary history. Similarly, the significant changes in MPD from species gains are more prevalent across the globe than from species loss, but the predominant pattern is that of unexpectedly strong increases in MPD , indicating that overall relatedness often decreases significantly through species projected to be gained under climate change. In addition, in those areas where the projected changes through species gain in Faith PD and in MPD are significant, these changes are often in opposite directions . We provide a more in-depth description of MPD results and their comparison to Faith PD patterns in the supplement.Focusing on species gains, we project those areas with significantly lower increases in Faith PD than expected to be most frequent at high northern latitudes, stretching across the entire Nearctic and Palaearctic realm, but also across parts of South America and Australia . Projected future changes for each phylogenetic diversity metric, Faith PD and MPD, overlap most in assemblages that may lose more phylogenetic diversity than if species were lost randomly and simultaneously gain more phylogenetic diversity than if species were gained randomly . This indicates that particularly high proportions of assemblages in most continents  are projected to experience major species reshuffling through both species losses and gains .. 4We find that including different measures of phylogenetic diversity (Faith PD and MPD) in future climate change impact assessments can help to identify species assemblages that might be under higher threat than projected changes in local SR alone would suggest. The projected impacts of climate change not only affect the amount of evolutionary history stored within species assemblages but might also have significant impact on the phylogenetic structure of species communities, which plays an important role in shaping ecological processes and ecosystem functioning because phylogenetic composition is usually linked to the composition in functional traits . Though Projected changes through species gain were notably stronger than those through species loss across the northern latitudes especially, confirming our expectation that these changes can be decoupled through strong and phylogenetically non-random range shifts. Going even further, our results showed that local species loss versus gain were strongly phylogenetically selective into opposite directions, especially in the Americas, Europe and Africa. In such assemblages, the net change in SR and in either phylogenetic metric might be very low, but the underlying changes in species composition are nonetheless high, indicating greater shifts in assemblage composition than would be apparent if projected gains and losses of species were not separately assessed. We conclude that disentangling the impacts of species gains and losses can aid in understanding of how assemblage-level phylogenetic diversity might be impacted by climate change, and with it, presumably, the diversity in functional traits and possibly ecosystem functioning. Important aspects of these impacts might be masked if only considering overall change in SR or phylogenetic diversity, or if only focusing on projected species losses.The projected changes in Faith PD and MPD differ significantly from expectations if random species are being gained or lost across large areas of the globe, indicating that the current phylogenetic structure of individual species assemblages might be widely changed in the future. This finding is in contrast with an earlier study that projected extinction risk from climate change to be evenly distributed across the phylogeny for some taxa within Europe . Differe (a)As expected, our results show that the spatial patterns of proportional changes in SR and amount of evolutionary history (Faith PD) are highly correlated on a global scale, thus the projected losses as well as gains in assemblage SR are largely reflected in decreases and increases in Faith PD, depending on the phylogenetic tree structure ,39. By cWe projected a clear spatial pattern where northern latitudes in North America and Eurasia were dominated by increasing phylogenetic clustering or diversification as a consequence of projected net gains in SR and accompanying changes in species composition. Across many assemblages in the high northern latitudes, net increases in evolutionary history were projected to be driven by significant Faith PD decreases caused by species losses on the one hand and less increase than expected under random species gain on the other hand. The resulting changes in species composition indicate the loss of some phylogenetically distinct species in combination with predominant gains of phylogenetically indistinct species. This result is not surprising as high northern latitudes are known to host fewer old lineages , but disIn addition, projected phylogenetic clustering in many of those areas indicated that the gained species are mostly related to each other or to the species already occurring in the assemblage, as shown by significant overall increases in relatedness in North America and patchy areas in northern Asia, for example. This projected combination of local gains of phylogenetically indistinct and closely related species with local loss of phylogenetically distinct and distantly related species is worrying if phylogenetically distinct species also exhibit unique features or traits , which mThe pattern of phylogenetic homogenization, caused by coinciding projected decreases in evolutionary history and increases in relatedness, occurred least frequently globally, in assemblages which were generally characterized by relatively small absolute changes in all three metrics . This was somewhat surprising as homogenization is often observed following anthropogenic disturbance, like habitat conversion through urbanization or agricultural expansion or intensification ,46. PoteIn contrast with the patterns in northern Eurasia and North America, projected increasing phylogenetic over-dispersion dominated the remaining continents with the exception of Australia, indicating decreases in both evolutionary history and relatedness with fewer species in future assemblages that are very distantly related. Assemblage change in these areas was generally driven by stronger decrease in evolutionary diversity than expected from species loss, and somewhat weaker effects from species gain that significantly increased relatedness. This indicated that across the world and especially in South America and southern Africa, projected local species losses predominate and remove phylogenetically distinct species, whereas projected species gains are less pronounced and add closely related species. These projected patterns indicate widespread local loss of old lineages especially in the southern hemisphere ,40, and  (b)Although there are several well-known sources of uncertainty inherent to SDMs, , we founFinally, the phylogeny needs to be interpreted as a hypothesis rather than at face value ,36, alth (c)At a global scale, the preservation of local phylogenetic diversity could be key to the resilience of biodiversity to environmental change . It rema


The nuclear receptors PXR, CAR, and FXR are activated by various ligands and function as transcription factors to control the expression of genes that regulate the synthesis and metabolism of androstenone and skatole. These compounds are produced in entire male pigs and accumulate in the fat to cause the development of a meat quality issue known as boar taint. The extent of this accumulation is influenced by the synthesis and hepatic clearance of androstenone and skatole. For this reason, PXR, CAR, and FXR-mediated signaling pathways have garnered interest as potential targets for specialized treatments designed to reduce the development of boar taint. Recent research has also identified several metabolites produced by gut microbes that act as ligands for these nuclear receptors ; however, the connection between the gut microbiome and boar taint development is not clear. In this review, we describe the nuclear receptor signaling pathways that regulate the synthesis and metabolism of boar taint compounds and outline the genes involved. We also discuss several microbial-derived metabolites and dietary additives that are known or suspected nuclear receptor ligands and suggest how these compounds could be used to develop novel treatments for boar taint. Nuclear receptors are a family of transcription factors that regulate the expression of genes controlling numerous physiological processes ,2. All nThe nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), and farnesoid X receptor (FXR) are class II nuclear receptors that form heterodimers with the retinoid X receptor (RXR) and bind to response elements primarily organized as direct repeats ,10.Initial studies characterized PXR as a ligand-dependent transcription factor for several genes belonging to the cytochrome P4503A (CYP3A) subfamily, activated by naturally occurring pregnane steroids such as pregnenolone and progesterone . PXR is CAR was first described as a constitutive receptor and was found to be inactivated by 3α-hydroxy, 5α-reduced androstane steroids . SeveralPXR and can modulate the production of bile acid metabolites that activate or repress PXR and CAR signaling pathways    3] thiazIn a clinical trial, 10 mg/kg of rifampicin was provided as a treatment for patients with primary biliary cirrhosis daily over 14 months; however, 37.5% of the patients withdrew from the study after six months of treatment due to rifampicin-induced side effects . CITCO (Numerous factors and physiological systems differentially regulate the development of boar taint in individual animals. Consequently, the response to most existing treatments for boar taint varies significantly between individual animals. We have summarized these factors and their impact in a recent review . This suNuclear receptor signaling pathways can regulate various physiological processes, from bile acid homeostasis to detoxifying drugs and other exogenous compounds. There is also evidence to suggest that the nuclear receptors PXR, CAR, and FXR regulate the expression of genes controlling the synthesis and metabolism of compounds that are responsible for the development of boar taint. However, these effects need to be evaluated using whole animal studies. Several endogenous compounds such as tryptophan metabolites, SCFAs, or bile acids, which are produced or metabolized by microbes in the gut, have been suggested to alter nuclear receptor signaling pathways. Based on this, it may be possible to prevent the development of boar taint by providing dietary sources of fermentable carbohydrates and related compounds to promote the activation or inhibition of PXR, CAR, or FXR-mediated signaling pathways by altering the basal production of these endogenous compounds. Several natural products commonly found in plants have been identified as nuclear receptor ligands in humans and mice. These compounds could potentially be included as a dietary supplement to selectively activate or inhibit nuclear receptor-mediated signaling events for the prevention of boar taint.


Increasing food demand coupled with climate change pose a great challenge to agricultural systems. In this review we summarize recent advances in our knowledge of how plants, together with their associated microbiota, shape rhizosphere processes. We address (molecular) mechanisms operating at the plant–microbe-soil interface and aim to link this knowledge with actual and potential avenues for intensifying agricultural systems, while at the same time reducing irrigation water, fertilizer inputs and pesticide use. Combining in-depth knowledge about above and belowground plant traits will not only significantly advance our mechanistic understanding of involved processes but also allow for more informed decisions regarding agricultural practices and plant breeding. Including belowground plant-soil-microbe interactions in our breeding efforts will help to select crops resilient to abiotic and biotic environmental stresses and ultimately enable us to produce sufficient food in a more sustainable agriculture in the upcoming decades. The increasing availability of industrial fertilizer and pesticides combined with the implementation of high yield plant varieties sparked the first Green Revolution in the middle of the twentieth century resulting in a massive increase in cereal yield worldwide. At that time, plant breeders focused on aboveground plant features, developing crops that would produce high yields under plentiful water and nutrient supply. While highly successful in parts of the world, with staple food yields doubling or even tripling, the Green Revolution brought little change to the areas worst affected by hunger and malnutrition Lynch . In addi3O+, CO2, O2) and organic compounds  into the soil (Oburger and Jones Plant species (and even varieties) are known to differ in their root resource acquisition efficiency (which we here define as mass unit nutrient or water taken up per unit root surface area)  as well as cell debris and sloughed-off root cap cells  as they forage for water and nutrients. These root exudates (and other rhizodeposits) play a central role in rhizosphere processes as they spark a cascade of feedback loops between roots, the associated microbiome and soil particles. Release mechanisms and functional importance of root exudates, particularly regarding nutrient mobilization and cycling as well as the interaction with microorganisms have already been discussed in numerous reviews to which we refer our reader for further details  growth conditions are still rather limited. Due to the complexity of soil structure, root system architecture and the multitude of processes that are immediately activated once the plant root releases C compounds into the soil, sampling of root exudates unaltered by these processes from soil-grown plants is highly challenging  poses a major C input into the soil, particularly for subsurface horizons. In addition, living roots and mycorrhizal hyphae and associated microbiota actively distribute C throughout the soil via the release of root exudates, mucilage, sloughed-off root cells and cell wall debris, depositing C into soil pores and onto mineral surfaces contributing to soil organic carbon (SOC) stabilization Frey . ConsequSufficient nutrient availability is essential for plant health and yield. However, our focus must lie not only on crop quantity but also on crop quality. Mineral and vitamin malnutrition – the so-called “hidden hunger” is considered one of the greatest challenges currently faced by human kind. The World Health Organization estimates that two billion people suffer from micronutrient malnutrition, like iron (Fe) and zinc (Zn), causing 7.3% of disease burden (Thompson and Amoroso Phaeseus vulgaris) and resulted in increased growth and P uptake compared to common bean lines either lacking in or expressing only one of investigated root phenotypes. However, a shallow root architecture was found to be less efficient in capturing N and it can also be a disadvantage under drought stress due to top soil drying. Dimorphic root phenotypes combining deep rooting with shallow rooting of the top soil are considered as more favorable particularly in climates facing drought periods (Lynch Growing (micro)nutrient-efficient crops is of particular importance in arid and semi-arid environments that are dominated by high pH and/or saline soils that are typically characterized by low and unbalanced phytoavailability of nutrients. At high pH nutrients are strongly fixed either by precipitation  or (particularly relevant for cationic micronutrients) by sorption to negatively charged mineral surfaces  and durum (T. turgidum L. conv. durum) genotypes in hydroponics under Zn deficiency suggested higher phytosiderophore exudation rates for Zn efficient genotypes  has been repeatedly demonstrated  uptake was found to have a major impact on rhizosphere pH  uptake . Nutrient deficiency induced rhizosphere acidification  genotypes in a calcareous soil as well as in nutrient solution culture, Gahoonia et al. (Lens culinaris) lines grown on the same calcareous soil, Gahoonia et al.  conditions to nutrient uptake is needed to successfully capitalize on these plant traits in the future.2 losses, regulation of plant diversity, as well as increasing soil aggregation and plant seedling survival. Another recent study suggests that inoculation of fungi could generally result in short-term increased plant productivity. This, however, comes at a potential cost of reducing biodiversity by anthropogenically increasing the abundance of mutualistic fungi that provide less of these ecosystem services noted above  are forming a symbiosis with mycorrhizal fungi, trading photosynthates for fungal-acquired nutrients  have been identified to efficiently solubilize phosphate from which plants can potentially benefit  and transforming it into ammonia (NH3) via the nitrogenase enzymes. In soil, these specialized bacteria either occur as free-living bacteria (e.g. Azotobacter), form associative relationships with host plants , or they can establish symbiotic associations with legumes and other plant species (e.g. Rhizobium harboured in nodules). In the latter, the plants provide photosynthetic C while the bacteroids deliver nitrogen fixed from the atmosphere to the host plants. It has been estimated that the global contribution of symbiotically fixed N2 is likely to be in the order of 20–22 million tons N per year  were found to be critical  is another important rhizosphere process that we can harness to improve plant nutrition. BNF is carried out by bacteria capable of fixing atmospheric nitrogen  of Azospirillum inoculum played a crucial role in achieving a positive yield effect. Research in the past decades however revealed that improved plant growth after inoculation with Azospirillum is most likely more related to its capacity to produce phytohormones, like indole-3-acetic acid, than to its N2 fixation activity   phenotype. While the idea is promising, following through will require a great scientific effort that needs to include mechanistic and applied studies as well as highly differentiated, interdisciplinary approaches that are tailored to different species/genotypes grown in several environmental conditions. While significant progress in understanding rhizosphere processes has been made in the last decades, past research often worked with simplified or artificial systems to break down the great complexity of the plant–microbe-soil environment and allow the identification of underlying mechanisms. Experiments using simplified systems were and still are crucial for stepwise elucidation of belowground interactions, however our advances in both, in-depth knowledge and experimental techniques, now enable us to conduct more holistic studies integrating a much wider range of relevant parameters. Results from these studies will be crucial in the future to further our understanding of rhizosphere processes, as a few pioneer studies already showed that conclusions drawn from simplified systems might not hold true when studying complexes environments.In summary, we suggest that including root traits and related belowground plant-soil-microbe interactions in our breeding efforts will help to select crops resilient to abiotic and biotic environmental stresses, like drought, flooding, poor nutrient availability, pest and pathogen attacks. In light of a growing world population and less predictable climatic conditions, we need to find solutions for crop production in a less resource-demanding manner which is also less detrimental to the environment. By focussing on a better understanding of individual plant traits, in conjunction with the associated microbiome and soil physicochemical properties as well as climatic conditions, we believe that it will be possible to further agroecological innovations in crop and soil management to increase soil health and reduce the footprint of agricultural practices.


Chronic musculoskeletal pain is a highly prevalent condition in older adults and is associated with a decrease in function, biological dysregulation and cellular aging, and increased risk of morbidity and mortality. Our previous work shows that a resilience index comprised of measures of recognized biobehavioral and psychosocial protective factors based on clinically validated norms  was positively associated with telomere length, lower levels of clinical pain and pain-related functional decline which, also correlated with pain-related brain structure. We will report the initial findings from our multi-centered, NIA RCCN funded study, Protective Resilience Index for Successful Aging in Musculoskeletal Pain (PRISM), which seeks to refine and validate a resilience index that is predictive of biological and pain-related outcomes. This work will lay the foundation for a resilience index that can be used in everyday clinical practice.


PRNP). While no disease-modifying therapy is currently available, genetic and pharmacological proofs of concept support development of therapies that lower PrP levels in the brain. In light of proposals for clinical testing of such drugs in presymptomatic individuals at risk for genetic prion disease, extensive nonclinical data are likely to be required, with extra attention paid to choice of animal models. Uniquely, the entire prion disease process can be faithfully modeled through transmission of human prions to non-human primates (NHPs), raising the question of whether NHP models should be used to assess therapeutic efficacy. Here we systematically aggregate data from N = 883 prion-inoculated animals spanning six decades of research studies. Using this dataset, we assess prion strain, route of administration, endpoint, and passage number to characterize the relationship of tested models to currently prevalent human subtypes of prion disease. We analyze the incubation times observed across diverse models and perform power calculations to assess the practicability of testing prion disease therapeutic efficacy in NHPs. We find that while some models may theoretically be able to support therapeutic efficacy studies, pilot studies would be required to confirm incubation time and attack rate before pivotal studies could be designed, cumulatively requiring several years. The models with the shortest and most tightly distributed incubation times are those with smaller brains and weaker homology to humans. Our findings indicate that it would be challenging to conduct efficacy studies in NHPs in a paradigm that honors the potential advantages of NHPs over other available models, on a timeframe that would not risk unduly delaying patient access to promising drug candidates.Prion disease is a fatal neurodegenerative disease caused by the conformational corruption of the prion protein (PrP), encoded by the prion protein gene , but the possibility of testing new prion disease drugs in prion-infected NHPs has never been formally evaluated. We therefore aggregated a comprehensive dataset of prion NHP studies from the literature and analyzed this dataset to determine whether, and under what conditions, this model could realistically be used to assess the efficacy of an experimental therapeutic. We find that while there is strong precedent for modeling prion disease in NHPs, a well-powered therapeutic study would be difficult to achieve on a realistic timeline due to the years-long timeframe of such studies and the lack of a well-established, predictable experimental system. We further find that the most tractable NHP models are not the most comparable to humans in terms of either brain size or prion protein gene homology, potentially reducing their utility. Finally, we suggest alternative study designs for gathering relevant animal data that may run a lower risk of delaying patient access to promising potential therapies. PRNP in humans [Prion disease is a rapidly fatal neurodegenerative disease of humans and other mammals. The pathogenic mechanism pivots on the conformational corruption of a host-encoded protein, the native prion protein or PrP, into a misfolded conformer, or prion, capable of corrupting other PrP molecules and killing neurons . Uniqueln humans , and acqn humans . The PrPn humans , and antn humans . This prThe prion field benefits from unusually faithful animal models. Direct inoculation of animals with prion-infected brain homogenate induces the full prion disease process in which a clinically silent incubation period gives rise to characteristic symptoms, histopathology, and biochemical features, followed by terminal illness . The inoGiven the rapid clinical progression of prion disease following symptom onset and ASO treatment data in mice suggesting an outsize benefit to early treatment , it has PRNP sequence relatively closer to the human gene sequence, which might permit testing of a human DNA or RNA-targeting therapy in a non-transgenic animal, and a larger brain size better suited to simulating drug delivery to the human brain. The likelihood of meeting these interests would have to be balanced against concerns about achieving adequate power to reach a meaningful clinical endpoint in a large, onerous model; ensuring that variables such as prion strain and transmission route remain faithful to clinically relevant disease paradigms; and ensuring that the length of such a study would not unnecessarily delay access to human treatments.The prospect of an unconventional clinical strategy draws special attention to the question of whether efficacy studies of such drugs in NHPs would be feasible or advantageous. Unlike other non-transgenic models, a number of NHP species have been shown susceptible to human prion strains on direct passage from human tissue. Other theoretical advantages could include a In order to evaluate the prospects for efficacy studies in NHPs and assess how the above interests and tradeoffs might be balanced, we set out to exhaustively catalog and analyze reported NHP models. We began with a systematic literature search to identify published articles containing original data following prion-infected NHPs to disease endpoints. We then aggregated and manually curated a dataset of individual animal cohorts and analyzed this dataset in order to i) determine how key experimental parameters in these models relate to prevalent forms of human prion disease, ii) analyze incubation times in these models and identify potential paradigms for efficacy studies, and iii) perform power calculations and assess the practicality and tradeoffs of various models.To ensure a comprehensive and reproducible search, the following search strategy was adopted  and/or published updates of experiments in progress. The rows were next manually de-duplicated with the goal of including any individual animal only once. This exercise identified both duplicated cohorts and cohorts for which insufficient details exist in the literature to determine whether or not they were elsewhere reported. Both were excluded, for a final count of N = 410 unique cohorts comprising N = 883 unique animals . The fulP value less than 0.05 was obtained. In each iteration, survival of untreated animals was sampled from a normal distribution with the reported mean and standard deviation, while survival of treated animals was sampled from a normal distribution with 1.5 times the reported mean and 1.5 times the reported standard deviation. For the "best case scenarios", all animals were assumed to reach endpoint; for the "other scenarios", a proportion (1-p) of animals were randomly censored, where p is the reported attack rate. Survival of treated and untreated animals was then compared using a two-sided log-rank test. For each iteration, the survival time of the longest-lived animal was also recorded. The expected study duration for each scenario was calculated as the average survival time of that longest-lived animal, across the 1,000 iterations.Power calculation assumptions are enumerated under Results. For each scenario, we bootstrapped N = 1,000 iterations and power was calculated as the percentage of those iterations in which a PRNP gene in each species, from transcription start to stop including intronic and untranslated regions, were exported from UCSC Genome Browser, except for spider monkey (Ateles geoffroyi), which was obtained from GenBank (PVHS01010010.1). Spider monkey, rhesus, and cynomolgus sequences, which are on the minus strand, were reverse complemented. The sequences were pairwise aligned to human PRNP using EMBOSS Needle [Sequences for the S Needle  with defS Needle  and openS Needle . Residuehttps://github.com/ericminikel/nhp_models.All analyses utilized custom scripts in R 4.0.4. Statistics in Figs Our systematic literature search (Methods) identified N = 76 publications reporting original data regarding prion disease endpoints in NHPs, totaling N = 410 distinct animal cohorts and N = 883 unambiguously unique individual animals . The temToday, intracerebral (IC) prion inoculation is considered the highest efficiency means of experimental transmission whether for primates  or rodenMost animals reviewed were followed with the intention of observing a clinical endpoint of either symptoms or terminal disease , followiMacaca fascicularis) were the most heavily represented primate species across studies, and squirrel monkeys (Saimiri sciureus) were the second-most studied (Pan troglodytes), while also well represented historically, are effectively no longer used for prion research following decisions by the NIH to phase out funding for chimpanzee research in 2013, and the U.S. Fish and Wildlife Service designation of all chimpanzees as endangered in 2015 [Cynomolgus macaques .Animals would be followed to terminal endpoint.The therapeutic intervention would convey a 50% increase in survival time.The outcome would be evaluated by log-rank survival test with a two-sided alpha = 0.05 statistical threshold.The study would last until the last animal reaches endpoint.PRNP transcript. Because antisense oligonucleotide therapeutics, a modality currently in development for prion disease, are 20 base pairs long and are generally intolerant to single mismatches, we calculated not only overall percent transcript identity, but also the percent of possible 20 base pair sequences that are 100% identical to the human sequence, a proxy for the probability of a drug designed for humans happening to match each species.Based on these assumptions, we calculated the expected study duration and statistical power  for each paradigm under either i) the best-case scenario from the literature or ii) any other available reports, and tabulated these along with iii) other considerations for each model . Other cThe best-case scenario for each paradigm would yield >90% power with study durations ranging from just over one to eight years, though it is possible that preliminary evidence of efficacy could be gleaned sooner. However, several caveats apply. First, as suggested by PRNP sequence identify, particularly as measured in terms of the multi-base pair stretches of identity likely to be required to support targeting with a human-relevant genetically targeted therapy.In addition, not all motivations for performing an NHP study are satisfied by the paradigms highlighted in PRNP variants have been proposed. Trials of experimental therapeutics in individuals with no detectable disease process may require unusually strong preclinical data, prompting an evaluation of all available tools.Here, we set out to assess the feasibility of conducting preclinical efficacy studies of experimental prion disease therapeutics in prion-infected NHPs. Efficacy studies in an NHP disease model are not typically gating for either human testing of, or approval of a new drug; for example, neurological ASOs recently advanced to the clinic have consistently done so based on demonstrations of efficacy in rodent disease models, complemented by pharmacokinetic, pharmacodynamic, and safety data from wild-type NHPs –50. HoweWe found that transmission of human prions to NHPs is well established, and has been achieved independently by multiple laboratories dating back to the 1960s. Inocula representing multiple human prion strains have proven transmissible to multiple NHP species by multiple routes of inoculation. In this sense, NHP models of prion disease have been deeply explored. Many prion-inoculated cohorts of NHPs, however, consisted of only one or two animals per experimental condition, and/or exhibited incomplete attack rates or highly variable incubation times. Restricting our analysis to cohorts of three or more prion-inoculated NHPs that developed terminal illness with a full attack rate reveals a more constrained universe of available models. Of these models, several paradigms in New World monkeys have achieved complete or near-complete attack rates in two years or less, with standard deviations of a few months. It is possible that a study in one of these species could offer reasonable power to detect a therapeutic effect within a few years using a clinically relevant prion strain such as sCJD.Nevertheless, our analysis highlights the challenges and limitations that such a study would face. Different studies have yielded incubation times of different magnitude and variability, potentially impacting study duration and statistical power . This vaPRNP sequence is composed of 20-meric runs of identity compared to the human gene. If a drug targeting the human gene is unlikely to show cross-reactivity by chance, cross-reactivity might only be achieved if it were prioritized in drug candidate selection, potentially compromising other drug parameters. While this analysis focuses by way of example of an oligonucleotide therapeutic targeting the prion protein RNA, the broader consideration of sequence identity is likely to be a consideration for other genetically targeted drug modalities.Meanwhile, it is debatable whether the New World monkeys with the most rapid incubation times observed here would honor all of the motivations for pursuing NHP studies to begin with. While their brain architecture may more closely mirror that of humans, their brain mass is a tiny fraction of that of a human brain (ranging from 0.6% to 8%), smaller than those of sheep, goats, pigs, and large dogs , so it iAn alternative to the use of NHP prion infection models is to use separate models to address each question about a drug. A possible scheme is outlined in Overall, the distribution of drug development activities across multiple more rapid and less costly models could allow a tighter feedback loop whereby insights from one experiment help to inform a follow-on experiment, and allow a greater diversity of experimental parameters such as prion strain, drug dose, dosing regimen, and time of administration to be varied. By contrast, an efficacy study in an NHP model would require an intense investment of time and resources in a single experiment.In summary, available data suggest that an NHP efficacy study of a prion disease therapeutic would be imaginable but daunting. The costs and benefits would need to be carefully weighed in light of both the drug type in question and the status of the drug development program to determine whether the scientific gains would outweigh the potential delay in advancing a therapeutic to human clinical trials.S1 TablesTable A: All prion NHP reports from which data were evaluated for inclusion in the present study. Table B: The full prion-infected NHP dataset used for analysis. Table C: All NHP species used in the studies evaluated for inclusion. Supplemental References.(XLSX)Click here for additional data file.