Guidelines For Interpretation Research Articles

Interpreting Burkholderia pseudomallei disc diffusion susceptibility test results by the EUCAST method

Interpreting Burkholderia pseudomallei disc diffusion susceptibility test results by the EUCAST method

E-PSMA: the EANM standardized reporting guidelines v1.0 for PSMA-PET

RationaleThe development of consensus guidelines for interpretation of Prostate-Specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) is needed to provide more consistent reports in clinical practice. The standardization of PSMA-PET interpretation may also contribute to increasing the data reproducibility within clinical trials. Finally, guidelines in PSMA-PET interpretation are needed to communicate the exact location of findings to referring physicians, to support clinician therapeutic management decisions.MethodsA panel of worldwide experts in PSMA-PET was established. Panelists were selected based on their expertise and publication record in the diagnosis or treatment of PCa, in their involvement in clinical guidelines and according to their expertise in the clinical application of radiolabeled PSMA inhibitors. Panelists were actively involved in all stages of a modified, nonanonymous, Delphi consensus process.ResultsAccording to the findings obtained by modified Delphi consensus process, panelist recommendations were implemented in a structured report for PSMA-PET.ConclusionsThe E-PSMA standardized reporting guidelines, a document supported by the European Association of Nuclear Medicine (EANM), provide consensus statements among a panel of experts in PSMA-PET imaging, to develop a structured report for PSMA-PET in prostate cancer and to harmonize diagnostic interpretation criteria.

Crop water status from plant stable carbon isotope values: A test case for monsoonal climates

Stable carbon isotope analysis is increasingly used in archaeology as an indicator of crop water status and/or water management regime. While the technique shows promise, robust modern baseline studies are required to inform and validate archaeological interpretations. Here, we test stable carbon isotope values as a crop water status proxy in a monsoonal climatic context for the first time. Specifically, we test the relationship between grain stable carbon isotope values (δ13Cgrain), water availability, irrigation and soil type in barley ( Hordeum vulgare L. (Zohary and Hopf.)) in north-west India, with the aim of deriving a locally-appropriate model for isotopic interpretation. We test this relationship across a substantial rainfall gradient (200–1000 mm/year) and find a negative logarithmic relationship between climatic water availability and δ13C. However, there is significant noise in the relationship, and we report δ13Cgrain variation of over 3‰ amongst samples drawn from similar climatic contexts. Soil type, irrigation type and irrigation frequency have no clear modifying effects. We conclude that: (1) barley stable carbon isotope values can act as an archaeological water status proxy in monsoonal areas, but will be most sensitive in areas receiving <450 mm rainfall per year; and (2) it is not possible to precisely infer water management regimes. On the basis of our results, we propose guidelines for archaeological barley stable carbon isotope interpretation in north-west India and analogous monsoonal climates.

Whole Genome Sequencing Applied to Pathogen Source Tracking in Food Industry: Key Considerations for Robust Bioinformatics Data Analysis and Reliable Results Interpretation.

Whole genome sequencing (WGS) has arisen as a powerful tool to perform pathogen source tracking in the food industry thanks to several developments in recent years. However, the cost associated to this technology and the degree of expertise required to accurately process and understand the data has limited its adoption at a wider scale. Additionally, the time needed to obtain actionable information is often seen as an impairment for the application and use of the information generated via WGS. Ongoing work towards standardization of wet lab including sequencing protocols, following guidelines from the regulatory authorities and international standardization efforts make the technology more and more accessible. However, data analysis and results interpretation guidelines are still subject to initiatives coming from distinct groups and institutions. There are multiple bioinformatics software and pipelines developed to handle such information. Nevertheless, little consensus exists on a standard way to process the data and interpret the results. Here, we want to present the constraints we face in an industrial setting and the steps we consider necessary to obtain high quality data, reproducible results and a robust interpretation of the obtained information. All of this, in a time frame allowing for data-driven actions supporting factories and their needs.

Perinatal Counseling at the Margin of Gestational Viability: Where We’ve Been, Where We’re Going, and How to Navigate a Path Forward

Perinatal Counseling at the Margin of Gestational Viability: Where We’ve Been, Where We’re Going, and How to Navigate a Path Forward

An inter-laboratory study of DNA-based identity, parentage and species testing in animal forensic genetics

The probative value of animal forensic genetic evidence relies on laboratory accuracy and reliability. Inter-laboratory comparisons allow laboratories to evaluate their performance on specific tests and analyses and to continue to monitor their output. The International Society for Animal Genetics (ISAG) administered animal forensic comparison tests (AFCTs) in 2016 and 2018 to assess the limitations and capabilities of laboratories offering forensic identification, parentage and species determination services. The AFCTs revealed that analyses of low DNA template concentrations (≤300 pg/µL) constitute a significant challenge that has prevented many laboratories from reporting correct identification and parentage results. Moreover, a lack of familiarity with species testing protocols, interpretation guidelines and representative databases prevented over a quarter of the participating laboratories from submitting correct species determination results. Several laboratories showed improvement in their genotyping accuracy over time. However, the use of forensically validated standards, such as a standard forensic short tandem repeat (STR) kit, preferably with an allelic ladder, and stricter guidelines for STR typing, may have prevented some common issues from occurring, such as genotyping inaccuracies, missing data, elevated stutter products and loading errors. The AFCTs underscore the importance of conducting routine forensic comparison tests to allow laboratories to compare results from each other. Laboratories should keep improving their scientific and technical capabilities and continuously evaluate their personnel’s proficiency in critical techniques such as low copy number (LCN) analysis and species testing. Although this is the first time that the ISAG has conducted comparison tests for forensic testing, findings from these AFCTs may serve as the foundation for continuous improvements of the overall quality of animal forensic genetic testing.

The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance.

Inefficiency of medical therapies used in order to cure patients with bacterial infections requires not only to actively look for new therapeutic strategies but also to carefully select antibiotics based on variety of parameters, including microbiological. Minimal inhibitory concentration (MIC) defines in vitro levels of susceptibility or resistance of specific bacterial strains to applied antibiotic. Reliable assessment of MIC has a significant impact on the choice of a therapeutic strategy, which affects efficiency of an infection therapy. In order to obtain credible MIC, many elements must be considered, such as proper method choice, adherence to labeling rules, and competent interpretation of the results. In this paper, two methods have been discussed: dilution and gradient used for MIC estimation. Factors which affect MIC results along with the interpretation guidelines have been described. Furthermore, opportunities to utilize MIC in clinical practice, with pharmacokinetic /pharmacodynamic parameters taken into consideration, have been investigated. Due to problems related to PK determination in individual patients, statistical estimation of the possibility of achievement of the PK/PD index, based on the Monte Carlo, was discussed. In order to provide comprehensive insights, the possible limitations of MIC, which scientists are aware of, have been outlined.

510 Contemporary trends in cesarean delivery rates and indications

The American College of Obstetrics and Gynecology (ACOG) introduced updated guidelines for labor management (2014) and fetal heart rate interpretation in an attempt to reduce cesarean delivery (CD) rates – especially the primary CD. We sought to describe CD rates and indications at a single center in order to assess the impact of these guidelines on trends in clinical practice. Retrospective cohort study of women ≥ 23 weeks gestation delivering at a single tertiary care referral center from 2013 - 2018. Demographic characteristics, mode of delivery, and main CD indication were ascertained by individual chart review. Main CD indications were defined as repeat CD, non-reassuring fetal status (NRFS), malpresentation, maternal indications (i.e. placenta previa or genital HSV), failed labor (any stage labor arrest), or other (i.e. fetal anomaly, elective). Polynomial (cubic) regression models were used to model rates of CD and main indications over time. Subgroup analyses further examined trends for nulliparous women. Of 24,637 women delivered during the study period, 24,050 women were included in the analysis; 7,835 (32.6%) had a CD. No clinically significant changes in the overall CD rate appeared during the study period (min 30.9% in 2014, max 34.6% in 2018). While CD for NRFS significantly changed over time - decreasing to a nadir in 2015 then rising (p=0.003), there were no differences in any other CD indications over time (Figure 1). When limited to nulliparous women, the rates of CD were similarly stable during the study period (min 30.7% in 2014, max 35.6% in 2013) and there were no differences in any primary CD indications over time (Figure 2). Despite the changes in labor management definitions and guidelines encouraging vaginal birth, rates of CD and indications for CD particularly failed labor, repeat CD, and malpresentation have not significantly changed over time. Studies should evaluate whether factors like patient preference and practice/provider variation contribute to the steady rate of CD.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance

PurposeBRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. MethodsWe have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. ResultsIntegration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. ConclusionHigh quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.

An Operational Framework for the Adoption and Integration of New Diagnostic Tests

The gap between medical research on diagnostic testing and clinical workflow can lead to rejection of valuable medical research in a busy clinical environment due to increased workloads, or rejection of medical research in the laboratory that may be valuable in practice due to a misunderstanding of the system‐level benefits of the new test. This has implications for research organizations, diagnostic test manufacturers, and hospital managers among others. To bridge this gap, we develop a Markov decision process (MDP) from which we create “adoption regions” that specify the combination of test characteristics medical research must achieve for the test to be feasible for adoption in practice. To address the curse of dimensionality from patient risk stratification, we develop a decomposition algorithm along with structural properties that shed light on which patients and when a new diagnostic test should be used. In a case study of a partner Emergency Department, we show that the conventional myopic medical criterion can lead to poor decision making in both research development and clinical practice. In particular, we find that specificity—long a secondary consideration and often overlooked in the research process—is, in fact, the key to effective implementation of new tests into clinical environments. This myopic approach can lead to overvaluing or undervaluing new medical research. This mismatch is accentuated when a simple (current) policy is used to integrate research into the clinical environment compared with our MDP’s policy—poor implementation of a new test can also lead to unnecessary rejection. Our framework provides easily interpretable guidelines for medical research development and clinical adoption decisions that can guide medical research as to which test characteristics to focus on to improve the chances of adoption.

Assessment of Illumina® Human mtDNA Genome assay: workflow evaluation with development of analysis and interpretation guidelines.

Mitochondrial DNA (mtDNA) is a small but significant part of the human genome, whose applicability potential has gradually increased with the advent of massively parallel sequencing (MPS) technology. Knowledge of the particular workflow, equipment, and reagents used, along with extensive usage of negative controls to monitor all preparation steps constitute the prerequisites for confident reporting of results. In this study, we performed an assessment of Illumina® Human mtDNA Genome assay on MiSeq FGx™ instrument. Through analysis of several types of negative controls, as well as mtDNA positive controls, we established thresholds for data analysis and interpretation, consisting of several components: minimum read depth (220 reads), minimum quality score (41), percentage of minor allele sufficient for analysis (3.0%), percentage of minor allele sufficient for interpretation (6.0%), and percentage of major allele sufficient for homoplasmic variant call (97.0%). Based on these criteria, we defined internal guidelines for analysis and interpretation of mtDNA results obtained by MPS. Our study shows that the whole mtDNA assay on MiSeq FGx™ produces repeatable and reproducible results, independent of the analyst, which are also concordant with Sanger-type sequencing results for mtDNA control region, as well as with MPS results produced by NextSeq®. Overall, established thresholds and interpretation guidelines were successfully applied for the sequencing of complete mitochondrial genomes from high-quality samples. The underlying principles and proposed methodology on the definition of internal laboratory guidelines for analysis and interpretation of MPS results may be applicable to similar MPS workflows, e.g. targeting good-quality samples in forensic genetics and molecular diagnostics.

Specifications of the variant curation guidelines for ITGA2B/ITGB3: ClinGen Platelet Disorder Variant Curation Panel

AbstractAccurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.

The genetic landscape of polycystic kidney disease in Ireland.

Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71-83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.

Preimplantation genetic testing (PGT) for copy number variants of uncertain significance (CNV- VUS) in the genomic era: to do or not to do?

To review cases of couples presented to our PGT-unit with copy number variants (CNVs) classified as variants of uncertain significance (VUS) in order to better understand their needs. Retrospective cohort study conducted in a tertiary medical-center, 2014-2019. We reviewed files of all couples applying for genetic counseling with CNVs classified as VUS. The main outcomes measured: number of VUS findings and their description, PGT-M procedures planned and performed, IVF cycles, clinical pregnancy, and live birth rates (LBR). VUS were classified according to the American-College of Medical-Genetics and Genomics classification at time of first consultation, and updated-December 2018. Twenty-four couples presented with a total of 30 VUS. Twelve couples (50%) had isolated VUS and 12 (50%) had VUS diagnosed in addition to a pathogenic mutation. Initially, nine findings (30%) were defined as VUS; eight (27%) as likely benign (b-VUS); and 13 (43%) as likely pathogenic (p-VUS). PGT-M was recommended for 17/30 CNVs (56.6%), 12 (70%) of which, isolated VUS. No couple had other indications for IVF. To date, nine couples performed PGT-M for isolated VUS; LBR per-couple-55.5%. Five couples performed PGT-M for both pathogenic findings and VUS, LBR-80%. After reviewing VUS classifications, 30% remained unchanged, 20% were more severely defined, and 50% less severely defined. The genomic era enables detection of VUS whose definition is subject to change as additional information becomes available. The uncertainty of variants' clinical significance and changes in VUS definition over time complicates genetic counseling. Revised guidelines for VUS interpretation and reevaluation of patient counseling before each pregnancy must be practiced when counseling them regarding the justification of PGT-M for their diagnosed VUS.

A Behavioral-Analytic Model for Assessing Stress in Firefighters.

Research has documented a number of acute and chronic stressors unique to the fire service. Due to the rise in mental health concerns in firefighters, there has been increased awareness of the negative effects of unmanaged stress. The present study employed a behavioral-analytic model to construct a brief screening measure of stress for this population: the Firefighter Assessment of Stress Test (FAST). Psychometric properties of the FAST were evaluated using data from active-duty firefighters throughout the United States. Results indicated the FAST has good internal reliability (α = 0.89), as well as good convergent and discriminant validity. Also, the factor structure of the FAST revealed three significant subscales reflective of stress associated with responding to calls, administrative difficulties, and being overworked. Scoring and interpretation guidelines were established to suggest when further assessment is warranted. The FAST offers a brief and valid method of self-assessment of current stress levels in firefighters. Information obtained from the FAST (i.e., overall stress level and domains) has the potential to facilitate more immediate identification and recognition of stress in firefighters than what has been possible to date. Moreover, heightened awareness of stress and its effects will hopefully culminate in expanded efforts directed toward stress reduction and intervention for firefighters and their families.

Phenotype and genotype analysis of recessive hereditary moderate sensorineural hearing loss caused by new mutations in OTOGL gene

Objective: To perform the phenotype and genetic analysis on two families with moderate sensorineural hearing impairment and determine the cause of deafness. Methods: The phenotype and genetic analysis was performed on the two hearing impairment pedigrees coming to Chinese PLA General Hospital from January 2014 to August 2020. DNA samples of the proband from family 1 and the parents from family 2 were collected and tested through next generation sequencing on all deafness genes, and Sanger sequencing was performed to verify the mutation sites. The reported pathogenic variants of the otogelin-like (OTOGL) gene, the autosomal recessive inherited deafness genes that cause moderate sensorineural hearing loss and the clinical manifestations of the deafness genes that have the similar expression location as the OTOGL gene were summarized and analyzed. Results: The pathogenic variants in the families were compound heterozygous variants in the OTOGL gene c.2773C>T/c.2826C>G (p.Arg925*/p.Tyr942*) and c.4455G>A/c.875C>G (Trp1485*/p.Ser292*), respectively. c.2773C>T was an already reported pathogenic variant causing hearing impairment in the literature, while c.2826C>G, c.4455G>A and c.875C>G were novel reported variant sites. The above four variants were classified as pathogenic variants according to the variant interpretation standards and guideline of the Amercian College of Medical Genetics and Genomics. Conclusions: Pathogenic variants in OTOGL gene is an important genetic factor leading to moderate sensorineural hearing loss. The newly discovered variant sites c.2826C>G, c.4455G>A and c.875C>G enrich the variant spectrum of OTOGL gene. The results of the current study provide a basis for genetic counseling of the related families and a new target for the treatment of hereditary hearing loss in the future.

From Delegation to Prescription: Interpretive Authority in International Investment Agreements

The proper allocation of interpretive authority between states and arbitral tribunals is central to current debates about investment treaty arbitration. States traditionally have given arbitrators broad latitude to interpret and apply international investment agreements. But as states gain greater experience with international investment arbitration, they are reclaiming interpretive authority from arbitrators as part of states’ broader reform efforts. To that end, states have devised at least four treaty-drafting techniques: interpretive guidelines, which tell tribunals how to interpret important treaty provisions, such as indirect expropriation, national treatment, and fair and equitable treatment; interpretive clarifications, which provide “greater certainty” on the meaning of investment protections in new treaties and interpretive gloss on existing treaties; interpretive indicators, which may tilt the interpretive balance toward the drafting states’ policy preferences, such as environmental protection; and interpretive markers, which record in the travaux preparatoires states’ preferred treaty interpretations. These drafting techniques can be enormously important. They may curtail arbitrators’ interpretive discretion, influence the interpretation of prior investment treaties, and even alter the outcome of arbitral cases. These techniques starkly illustrate the move from a traditional “delegation” model of IIAs to a more “prescriptive” model. Given their increasing use, these techniques are likely to significantly affect the development of international investment law and arbitration for years to come.

Feasibility of Use of the 8th Edition of the American Joint Committee on Cancer Staging for Head and Neck Cancers in Indian Scenario: An Evaluative Study.

Introduction:Inclusion of depth of invasion (DOI) and a separate classification for human papillomavirus (HPV)-associated Oropharyngeal Cancers (OPCs) are two of the many major changes in the 8th edition of the American Joint Committee on Cancer staging system. After more than 2 years of implementation, the authors found the need to evaluate if the Indian clinicians found it feasible to apply the system in their practice and if the same has influenced their decision-making.Methods:The survey was done in the form of a questionnaire which was distributed personally and via the internet to 100 clinicians. Seventy-two clinicians responded to the questionnaire. The results were analyzed and frequency distribution was computed.Results:Eighty-three percent of the clinicians experienced that palpation of the tumour was not a reliable method to determine the DOI. The common issues stated by the clinicians were difficulty in assessing DOI in certain subsites of the oral cavity (most commonly retromolar trigone–83%), inability to determine DOI in patients with trismus, and inability to correlate pathological and clinical DOI. Thirteen percent of the clinicians did not rely on radiological tools for measuring the DOI. Seventy percent of the clinicians did not perform a P16 assay for patients with oropharyngeal cancers. Fifty percent of the clinicians preferred chemoradiotherapy for early HPV positive oropharyngeal cancers.Discussion:Based on the results of the survey, the authors recommend a need for more interpretative guidelines and methods for determining the DOI. The authors also emphasize the need for determining HPV status for all oropharyngeal carcinomas.

Rugosidades: desvelamentos para urbanização turística e patrimônio edificado

This paper discusses the concept of “roughness” as the driving principle in the analysis of the rela‑ tionship between tourism development and built cultural heritage. It’s a theoretical reflection of an exploratory and descriptive nature that aims at synthesizing existing knowledge while providing new interpretative and analytical guidelines. Working from previous studies it was possible to identify the dialectics of the relationship between cultural heritage and tourism development with perspectives centering on two classification catego‑ ries, their intrinsic value and their market value. The study presents a re‑think of the concepts of roughness and heritage used in urban planning aimed at re‑interpreting urban space for tourism, re‑appraising their possible application to heritage sites in the city. The results may open up new perspectives for urban planning and roughness and balance out the advantages and disadvantages of re‑working the city space for tourism.

Application of Indian Academy of Cytologists Guidelines for Reporting Serous Effusions: An Institutional Experience.

Background:Recently, the Indian Academy of Cytologists (IAC) has published the guidelines for interpretation and reporting of serous effusions. Till date, there are no studies on its applicability.Aims:The present study was carried out to assess the feasibility of applying the IAC reporting categories to effusions, determine the frequency, and provide an estimate of the risk of malignancy (ROM) for individual diagnostic categories.Materials and Methods:All cases of serous effusion fluids reported in the year 2019 were retrieved from the archives and reassigned as per the IAC diagnostic categories. The clinical and histopathological follow-up information was obtained wherever possible.Results:A total of 1340 effusion samples were received from 1085 patients. There were 561 (51.7%) males and 524 (48.3%) females. Majority were pleural (1066, 79.5%), followed by peritoneal (187, 14%) and pericardial (87, 6.5%) effusions. The age ranged from 7 months to 92 years. There were 35 (2.6%) samples in category 1 (non-diagnostic), 954 (71.2%) in category 2 (benign), 17 (1.3%) in category 3 (atypical), 59 (4.4%) in category 4 (suspicious for malignancy) and 275 (20.5%) in category 5 (malignant). The estimated ROM in serous effusion samples was 20% for category 1, 16.7% for category 2, 50% for category 3, 94.4% for category 4 and 100% for category 5.Conclusions:The categorization of serous effusion cytology samples as per the IAC diagnostic categories and as per the reporting format developed by the IAC is feasible and the management recommendations are mostly appropriate.