WikiGuidelines

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Guidelines for Diagnosis and Management of Infective Endocarditis in Adults

A WikiGuidelines Group Consensus Statement

Emily G. McDonald, MD MSc, Gloria Aggrey, MD, Abdullah Tarık Aslan, MD, Michael Casias, PharmD, BCIDP, AAHIVP, Nicolas Cortes-Penfield, MD, Mei Qin (Denise) Dong, Pharm.D., Susan Egbert, PharmD, Brent Footer, Pharm.D., Burcu Isler, MD, FRACP, Madeline King, Pharm.D., Mira Maximos, PharmD, MSc, ACPR, Terence C. Wuerz, MD MSc, Ahmed Abdul Azim MD, Jhongert Alza-Arcila, MD, Anthony D Bai MD, Michelle Blyth, MD, MSPH, Tom Boyles, MD, Juan Caceres, MD, Devin Clark, MD, Kusha Davar, MD, MBA, MS, Justin T Denholm, BMed, PhD, Graeme Forrest, MBBS, Bassam Ghanem, PharmD MS BCPS, Stefan Hagel, MD, MS, Alexandra Hanretty, Pharm.D., Fergus Hamilton, MRCP, Philipp Jent, MD, Minji Kang, MD, Geena Kludjian, PharmD, BCIDP, Tim Lahey, MD, MMSc, Jonathan Lapin, Pharm.D., Rachael Lee, MD, MSPH, Timothy Li, MRCP, Dhara Mehta, PharmD, BCIDP, Jessica Moore, Pharm.D., M.S., Clayton Mowrer, DO, MBA, Georges Ouellet, MD, Rebecca Reece, MD, Jonathan H. Ryder, MD, Alexandre Sanctuaire, PharmD, MSc, James M Sanders, PharmD, PhD, Bobbi Jo Stoner, PharmD, BCPS, Jessica M So, MD, MS, MPH, Jean-François Tessier, B.Sc., M.Sc., Raghavendra Tirupathi, MD FIDSA, Steven Y.C. Tong, MBBS, PhD, Noah Wald-Dickler, MD, Arsheena Yassin, Pharm.D., Christina Yen, MD, Brad Spellberg, MD, Todd C. Lee, MD MPH

Question

Using the WikiGuidelines approach to the construct of clinical guidelines, how often can clear recommendations be made in the diagnosis and management of adult bacterial infective endocarditis?

Findings

In this systematic review only 1 of 17 questions had sufficiently high-quality data to allow for a clear recommendation. Oral transitional therapy is at least as effective as IV-only therapy for the treatment of infective endocarditis.

Meaning

These results suggest that this novel, egalitarian methodology enables a clear separation of established care standards based on hypothesis-confirming evidence from practice preferences that are based on lower quality or no evidence

Infective endocarditis (IE) is an ancient illness that can be difficult to diagnose and treat leading to substantial morbidity and mortality even in the modern era. The literature regarding the management of IE spans decades but features few high quality randomized clinical trials. This second WikiGuidelines Consensus Statement addresses the evidence-based management of IE. The guideline was drafted by an independent, international consortium of medical professionals who previously established a collaborative method to construct pragmatic, real-world, clinical practice guidelines (www.wikiguidelines.com (Spellberg et al., 2022). WikiGuidelines provide Clear Recommendations when reproducible, high-quality data and/or hypothesis-confirming evidence is available, and otherwise provide comprehensive Clinical Reviews summarizing different clinical approaches. WikiGuidelines offer clinician insights and are not intended to establish care mandates or medicolegal standards of care, nor to replace individual clinician judgment.

The intended end-users are clinicians providing patient care across diverse settings (academic, community-based) and socio-economic statuses (low-, middle-, or high-income countries), with varied experience (generalists or specialists). We incorporate the principles of high value care (i.e., right care, right place, right cost) and healthcare quality (i.e., timely, safe, effective, efficient, equitable, patient-centered). As such, considerations of resource utilization, systems-based practice, reduction in healthcare waste, and harm reduction are intrinsic.

Feedback is solicited from many licensed practitioners to move away from guidelines constructed by subspecialty member organizations by invitation only. This allows for a more inclusive, broader representation of everyday care providers from across the world. We seek to change the traditional guidelines practice of creating care mandates based on expert opinion rather than hypothesis-confirming data, which risks societal-level harm by setting incorrect standards of care (Packer, 2016; Spellberg et al., 2021; Spellberg & Shorr, 2021; Wright et al., 2021).

Following electronic polling of clinicians, we identified the next most preferred topic that could benefit from the WikiGuidelines approach: the diagnosis, prophylaxis, antibiotic therapy, and team-based management of bacterial IE in adults.

KEY POINTS

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METHODS

RESULTS

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This guideline was crafted in accordance with the WikiGuidelines charter and follows SQUIRE 2.0 (Revised Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0), n.d.). The authorship team included 51 members from 10 countries (listed in the Supplement), including 31 MDs and 16 PharmDs with expertise in internal medicine, hospital medicine, infectious diseases and microbiology, cardiac surgery, cardiology, radiology, nephrology, and pharmacology. The charter specifies the process for selection of members (authors), conflict resolution, and for evidentiary and consensus standards used to review the literature. The GRADE system for evaluating the strength of evidence was replaced with a dichotomized approach of providing either clear recommendations or clinical reviews, due to published concerns with GRADE including risk of bias, poor interrater reliability, and the dissociation between strength of recommendation and quality of evidence.(Guyatt et al., 2008; Shaneyfelt & Centor, 2009; Wright et al., 2021)

High quality, hypothesis-confirming data enable a Clear Recommendation and are based on at least one properly conducted, adequately powered randomized controlled trial (RCT) AND at least one other concordant, prospective, controlled clinical study (either a second RCT, a quasi-experimental pre-post study, a pragmatic clinical trial, or a carefully conducted historically controlled study). In the absence of such data, to provide guidance that is permissive rather than proscriptive, WikiGuidelines provides Clinical Reviews that discuss clinical approaches, comparing risks and benefits. Recognizing the core ethical and clinical principle of “first do no harm,” consensus on routinely avoiding unsubstantiated care is permitted even in the absence of a Clear Recommendation.

On April 29th, 2022, interested members were asked to submit their top questions on the diagnosis and management of endocarditis. Questions were thematically grouped into topic sections and individual members volunteered to collaboratively author sections of interest. Sections had 1-2 team leaders and drafting team members who conducted literature reviews using PubMed or alternatives. There were no restrictions to searches, and all languages and dates were considered for inclusion. Following internal revision by topic group members, initial versions were revised by the first and senior authors and then circulated to all members participating on the guideline for further refinement. Drafting members could post questions electronically (social media or email) to receive open-source feedback on how to construct answers to questions that lacked hypothesis-confirming data. The second open round of revisions led to a final version of each topic which then underwent a third round of revisions by all members. When feasible, for answers with more than one relevant study, meta-analysis was conducted using Stata Version 17.0 (StatCorp LP, USA).

KEY POINTS

ABSTRACT

INTRODUCTION

RESULTS

DISCUSSION

CONSCLUSIONS

ARTILCE INFO

Part 1: Establishing the diagnosis of infective endocarditis

KEY POINTS

ABSTRACT

INTRODUCTION

METHODS

DISCUSSION

CONSCLUSIONS

ARTILCE INFO

The reference standard for diagnosis of IE is pathological confirmation. However, such information is virtually never available at the time when empiric therapeutic decisions must be made, and unless the patient undergoes surgical replacement of a valve remains unavailable to confirm the diagnosis later. Several schemas have been developed over the years to guide clinicians in the diagnosis of IE absent pathological confirmation (Supplemental Table 1). Five of the seven schema are based on the original Duke criteria and an iterative process that has aimed at improving sensitivity. Such schemas typically include clinical, microbiological, and imaging (e.g., echocardiography or positron emission tomography [PET]) criteria. Schemas such as the modified Duke criteria (updated in 2023 to the Duke-ISCVID criteria (Fowler et al., 2023)) are widely used and convenient for clinicians facilitating real-time diagnostic and therapeutic decision-making. However, there are no high-quality studies that definitively determine which diagnostic schema is most accurate, nor have head-to-head studies compared clinical outcomes between schemas. Studies that have reported the diagnostic accuracy have important limitations including: retrospective designs, heterogeneous reference standards, and patient populations at variable risk of IE. It is therefore unclear how well schemas extrapolate to diverse care settings. Thus, no recommendation can be made regarding which, if any, are preferred for use. However, a structured approach to the diagnosis of IE is preferrable clinically and essential to guide research. Since most research studies apply the modified Duke criteria, these criteria likely accord with what most clinicians use.

Q2 How should blood culture parameters be used to inform suspicion for infective endocarditis?

KEY POINTS

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INTRODUCTION

METHODS

DISCUSSION

CONSCLUSIONS

ARTILCE INFO

Observational data suggest time-to-positivity (TTP) of blood cultures of less than 12 hours is associated with Staphylococcus aureus IE and independently predicts hospital mortality(Kahn et al., 2021). A similar study found that a shorter TTP was associated with IE in monomicrobial Enterococcus faecalis bacteremia (OR 13; 95% CI: 4.4–38 in multivariate analysis)(Oldberg et al., 2021). TTP is likely influenced by the blood culture machine/bottles being used and by pre-exposure to antibiotics (Butler-Laporte et al., 2020).

Observational data suggest that with modern culture techniques

, a standard 5-day incubation for blood cultures is adequate for almost all causes of IE (Fihman et al., 2021; Lourtet-Hascoët et al., 2019) Prolonged incubation could be considered in patients with prosthetic valve endocarditis (PVE) when Cutibacterium acnes is suspected (Fida et al., 2019; Fihman et al., 2021; Lourtet-Hascoët et al., 2019).

Two large observational studies suggest that the maximum yield for recovering a pathogen from blood cultures is achieved with 3 (96(Cockerill et al., 2004)-98% (Lee et al., 2007)) to 4 sets (99.8%(Lee et al., 2007)) over 24 hours, with each set comprised of 2 x 10mL filled bottles. Where possible, these should be taken prior to antibiotics as the yield of blood cultures decreases after antibiotics are received (Cheng et al., 2019). The relationship between the number of positive blood culture sets and the diagnosis of IE requires additional study; however, growth in multiple versus single blood culture bottles is associated with IE in Staphylococcus aureus bacteremia and growth in 3 or more bottles is associated with IE in Enterococcus faecalis bacteremia(Dahl et al., 2019; Go et al., 2022).

Q3-4. How can the diagnoses of Bartonella and of Coxiella Burnetii (Q Fever) infective endocarditis be established?

There are limited published data to inform the accuracy of diagnostic testing for Bartonella IE, and published C. Burnetii data has come from one center. While it may be reasonable to use an IgG titer cut-off of ≥1:800 as diagnostic evidence of Bartonella IE, clinicians should be aware that the dataset supporting accuracy of this cut-off is limited(Fournier et al., 1996), patients who do not have IE can have titers as high as 1:800 or higher, and patients can have lower titers but still have Bartonella as an etiology for IE.

The widely used serological cut-off to diagnose Q fever IE is a Phase I IgG antibody titer of 1:800. However, validation of this titer cut-off was based on a 20 patient case series,(Fournier et al., 1996) and no high-quality published studies have established its accuracy.

In most cases of suspected IE, obtaining an echocardiogram represents usual care; nonetheless, like any test, echocardiography should be ordered when it will inform management decisions.

Both the pre-test probability of IE and study quality strongly affect the impact of transthoracic echocardiography (TTE) on patient management. A negative TTE may be adequate to rule out native valve endocarditis (NVE) if the initial pre-test probability (Fowler et al., 2003; Østergaard et al., 2022) is low (e.g., <10%), or with a high-quality study, even if the pre-test probability is moderate (e.g., <25%).

Transesophageal echocardiography (TEE) is more sensitive than TTE for the diagnosis of IE. A TEE is most useful in specific scenarios:

1) to reduce the possibility of NVE where an unacceptably high post-test probability remains after a negative TTE (e.g., 5-10%) and where eliminating the diagnosis will change patient management.

2) in the evaluation of PVE where TTE has a lower sensitivity; and/or

3) to facilitate surgical planning or to evaluate for specific complications (e.g., perivalvular abscess).

Not all centres have timely access to TEE (or TTE). Decisions regarding transfer to obtain an echocardiogram in resource-constrained settings need to be individualized.

Numerous clinical scoring systems have been developed to better identify patients who may benefit from invasive testing with transesophageal echocardiogram (TEE) (Supplemental Table 3). Many have demonstrated high negative predictive values, which could be useful for resource stewardship. However, clinical prediction scores have important limitations. They have only been evaluated in retrospective studies, in some cases with relatively small numbers of patients with IE due to a single causative pathogen, with varied reference standards. Furthermore, there may be considerable selection bias and included patients may not be generalizable. Clinical prediction scores for IE have never been applied in a prospective study to demonstrate improved clinical outcomes or resource utilization. Scores may also be more complex than clinical criteria commonly used in clinical practice (e.g., multiple positive blood cultures, time to clearance of bacteremia, and the presence of IE sequelae). Thus, the data are insufficient to make a Clear Recommendation.

Numerous observational studies have evaluated the accuracy of 2-[18F]-fluorodeoxyglucose (18-FDG)-positron emission tomography (PET)/CT for the diagnosis of NVE, PVE and cardiac device-related IE (CDIE). Meta-analyses have reported the sensitivity of 18F-FDG-PET/CT for NVE as poor, especially compared to PVE and CDIE, however specificity remains high. Specifically, the pooled sensitivity/specificity of 18F-FDG-PET/CT for NVE was reported as 31%/82% versus 73%/80% for PVE and 87%/94% CDIE (Albano et al., 2021; Juneau et al., 2017; Wang et al., 2020). Given its low sensitivity, a negative 18F-FDG-PET/CT cannot rule out a diagnosis of NVE, even in cases where there is a low pre-test probability. It may be reasonable at appropriately resourced centers to use 18F-FDG-PET/CT for strongly suspected cases of PVE or CDIE in the presence of a negative or non-diagnostic TTE/TEE.

The ability of 18F-FDG-PET/CT to affect clinical outcomes has not been assessed for IE specifically, but observational studies have suggested 18F-FDG-PET/CT may increase detection of occult, secondary seeded sites of infection during S. aureus bacteremia (Thottacherry & Cortés-Penfield, 2022). 18F-FDG-PET/CT is resource-intensive, not routinely available in all centers, and exposes patients to ionizing radiation and whether use improves outcomes remains unknown.

Part 2: Establishing the diagnosis of infective endocarditis

Part 3: Prophylaxis

Antibiotic prophylaxis of endocarditis risks toxicity and selects for antibiotic resistance, causing societal-level harm.(Beacher et al., 2015) Consequently, WikiGuidelines authors prefer limiting prophylaxis to patients who both are perceived to be at higher risk for IE (prosthetic cardiac valves or retained prosthetic material used for cardiac valve repair; cardiac transplant recipients with valve regurgitation; congenital cyanotic heart diseases- unrepaired or with residual shunt; and those with a prior history of IE(Wilson et al., 2021) ) and who are undergoing dental procedures where there is likely a greater risk of bacteremia (e.g., manipulation of the gingival tissue or periapical region around the teeth, or perforation of the oral mucosa).(Wilson et al., 2021) Of note, a 2022 study by Vähäsarja et al. found no increased incidence of oral streptococcal IE among high-risk individuals following a recommendation to no longer administer antibiotic prophylaxis in dentistry.(Vähäsarja et al., 2022) More evidence is required to support any recommendation regarding prophylaxis for gastrointestinal, genitourinary, respiratory, or skin and soft tissue procedures.(Thornhill et al., 2022) If used, the risks of antimicrobial prophylaxis may be partly mitigated by using a single dose rather than longer courses.

Q2. Which antibiotics are appropriate for antibiotic prophylaxis to prevent infective endocarditis?

No high-quality data inform relative efficacy of various prophylaxis regimens to prevent IE. Nevertheless, given the known microbiology of procedurally related cases of IE, it is rational to select prophylactic antibiotics that are active against viridans group Streptococci (VGS). Oral administration is preferred, with penicillins and cephalosporins associated with a lower rate of Clostridioides difficile infection when compared to clindamycin.(K. A. Brown et al., 2013) There are no RCTs in support of one agent vs. another; however, amoxicillin seems to be the most commonly used and carries the lowest risk of adverse events overall (Table 1).(Thornhill et al., 2019; Wilson et al., 2021)

Part 4: Treatment

Little high-quality evidence is available to guide selection of empiric therapy for known or suspected IE. Observational studies have suggested that IE outcomes may be improved by consulting infectious diseases experts.(Bai et al., 2015; Yamamoto et al., 2012) Empirical regimens are generally selected to cover the most likely potential causes based on the history and physical examination incorporating risk factors or clues for the source of infection and/or local antimicrobial resistance patterns (which may differ by geographic location). In general, a combination of vancomycin or daptomycin (to cover MRSA, Enterococcus sp., and in the case of prosthetic valve, coagulase negative staphylococci(Murdoch et al., 2009)) and a beta-lactam like ceftriaxone (if suspecting an odontogenic or gastrointestinal focus) or cefazolin (if suspecting methicillin susceptible Staphylococcus aureus [MSSA]) may be reasonable, although alternative regimens are also possible and there is almost no direct comparative evidence (Table 2; Supplemental Table 10). Absent comparative outcomes studies, some authors prefer a daptomycin dose of 8-10mg/kg if S. aureus is suspected(Jones et al., 2021) and 10-12mg/kg if enterococcus is being targeted.(Adema et al., 2022) To minimize harm, the aminoglycosides and rifampin are best reserved for definitive therapy, if used at all.

Q2. What are potential definitive intravenous-based treatment options for infective endocarditis?

Definitive antibiotic therapy recommended for IE depends on the etiologic organism, its susceptibility, patient factors (e.g., comorbidity, allergy), and whether the infection is of a native or prosthetic valve. This treatment regimen complexity has limited the availability of high-quality comparative outcomes studies. In general, the addition of adjunctive agents (e.g., beta-lactam, aminoglycosides, rifampin, etc.) requires a careful consideration of the risks and benefits and an acknowledgement of the limitations of the evidence.(Ryder et al., 2022) Most WikiGuidelines authors suggest against routine use of adjunctive aminoglycosides because of a lack of evidence of benefit with a demonstrable risk of harm (discussed in the Supplement, and for S. aureus NVE, data for death, relapse, and renal failure are meta-analyzed and presented in Supplemental Figure 2). Options for definitive intravenous therapy by organism are presented in Table 3 with nuanced discussions in the Supplement.

Q3. Can oral antimicrobial therapy be used to treat infective endocarditis?

Three randomized controlled clinical trials have established that transition from initial IV-therapy to oral therapy is at least as effective as IV-only therapy for the treatment of IE.(Heldman et al., 1996; Iversen et al., 2019a; Stamboulian et al., 1991) These results are also supported by pharmacologic data demonstrating that many oral antibiotics achieve adequate levels in blood to exceed the minimum inhibitory concentrations (MICs) of target pathogens, as well as numerous observational studies of oral therapy for IE demonstrating favorable outcomes.(Wald-Dickler et al., 2022) Importantly, IV-only therapy has never been established to be superior to modern oral antimicrobial therapy in any clinical trial or observational study of patients with IE. Therefore, after factoring in considerations presented in the Detailed Responses in the Supplement, transition to oral therapy from initial IV therapy is a reasonable option for treating patients with IE.

Q4. If oral antimicrobial therapy is used in the treatment of infective endocarditis, are there preferred agents, is a specific duration of IV lead-in therapy necessary, and what are reasonable clinical criteria for patient selection?

Not all oral antimicrobial agents are likely candidates for treatment of IE. Historical experience suggests that older sulfonamides, tetracyclines, and macrolides may lead to poor outcomes perhaps related to low achievable blood levels relative to target MICs.(Finland, 1954a, 1954b; Roantree, 1955) Trimethoprim-sulfamethoxazole was inferior as a lead-in option for the treatment of staphylococcal IE in two RCTs.(Markowitz et al., 1992; Paul et al., 2015) If oral therapy is used, it is rational to select antibiotics demonstrated to have efficacy in published studies (Table 4).(E. Brown & Gould, 2020; Davar et al., 2023; Martí-Carvajal et al., 2020; Rezar et al., 2021; Spellberg et al., 2020; Wald-Dickler et al., 2022) It is unclear whether dual regimens, such as those used in the POET study(Iversen et al., 2019a), are required, as other data have demonstrated favorable outcomes with certain monotherapy regimens (Table 3; Supplemental Tables 11 and 12). It is also unclear to what extent intravenous lead-in therapy is needed prior to transitioning to oral therapy, as studies have used a wide range of intravenous lead-in prior to oral therapy, including one RCT with no IV lead-in.(Heldman et al., 1996) Reasonable patient selection criteria for oral therapy may include: 1) clinical stability with no immediate indication for procedural source control or cardiac surgery; and 2) bacteremia has cleared, or is clearing without the need for source control; and 3) an oral antibiotic regimen is available to which the etiologic organism is susceptible in vitro and which is supported by published clinical data; and 4) the patient is likely to absorb the antibiotic from the GI tract; and 5) there are no socioeconomic determinants of health or inequities rendering IV therapy the preferred route.

Q5. Can oral antimicrobial therapy be used to treat infective endocarditis?

Evidence to support durations of treatment for IE are almost entirely observational, and most durations are based on historical practice. One RCT established that penicillin-susceptible streptococcal endocarditis treated with 2 weeks of combination therapy with ceftriaxone and gentamicin resulted in similar outcomes as 4 weeks of ceftriaxone monotherapy (Sexton et al., 1998) .Whether combination therapy is necessary is addressed in the Detailed Responses (Supplement).

For other pathogens, and in absence of data, the historical practice has been to treat staphylococcal and enterococcal left-sided endocarditis for 6 weeks and HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella) endocarditis for 4 weeks. Recommendations to treat PVE for 6 weeks are also based on opinion rather than high quality data. Ongoing RCTs SATIE (Olmos et al., 2020) and POET II (Østergaard et al., 2020) should help to establish optimal durations.

For uncomplicated right-sided IE caused by MSSA (defined as lacking intra-cardiac or systemic complications of infection), prospective observational studies and one RCT conducted in the PWID population(Ribera et al., 1996) suggest that 2 weeks of combination antibiotic therapy might result in similar cure rates as longer courses. However, both 2-week treatment groups in the only RCT had a lower-than-expected combined treatment success in the intention to treat population (mean 72% [95% CI 63-81%]) and the observational studies all had major limitations. Optimal durations of therapy for uncomplicated right-sided IE outside of the PWID population and/or caused by other pathogens are unknown. In the absence of evidence, WikiGuidelines authors feel it may be reasonable in carefully selected cases (see Detailed Responses in Supplement) to use a similar duration of therapy for other pathogens as for MSSA. For patients with complicated right-sided IE, no data are available to guide duration of therapy, and longer courses are often used without any supporting evidence.

Infective endocarditis is associated with high morbidity and mortality. Despite an extensive literature discussing the management of IE, we found that most aspects of diagnosis and management are based on historical practice and small, outdated, observational studies. High quality studies can inform only one clear recommendation: oral transitional antibiotics for the treatment of IE. This paucity of high-quality evidence will change with the arrival of results of several much-needed ongoing RCTs.

The major limitation of this Consensus Statement is the lack of high-quality studies. The entire area of treatment in terms of antibiotic prophylaxis, empiric therapy, selection of optimal antibiotic classes, and almost all permutations of durations of therapy are based on case series or small observational studies. Again, very few (or no) head-to-head trials of different therapeutic options exist. It was striking to observe how much of the management of IE is based currently based on historical practice or expert opinion. Although oral antibiotics to complete treatment of IE have the strongest evidence, this approach still lags in clinical practice.

Much of the observational evidence also has very important limitations with respect to the diagnosis of IE as the criterion standard varies between studies, there is obvious selection and immortal time bias present, and few studies use pathologically confirmed IE.

This WikiGuideline highlights the lack of high-quality evidence that supports most of the modern practices in diagnosis and management of bacterial IE in adults. This Consensus Statement represents data available as of June 1st, 2023. Clinicians who believe other evidence should be considered are encouraged to contact the authors to propose revisions to the online living version of this guideline. As previously stated, no clinical trial or knowledge synthesis can extrapolate to all possible patient care scenarios; hence, this guideline is not intended to establish medicolegal standards of care or replace clinician judgment for individual patients.

EGM and TCL had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

We also wish to thank Dr. Gabriel Vilchez for providing critical insights to the crafting of this WikiGuideline.