An Investigation of Mortality Associated With Comorbid Pneumonia and Thrombocytopenia in a Rural Southwest Missouri Hospital System.

BACKGROUND: Pneumonia places a significant burden on individuals and society, contributing to a substantial number of hospital admissions, emergency department visits, deaths, and healthcare costs each year. Comorbidities can greatly increase the risk of poor outcomes when associated with pneumonia. One comorbidity that has yet to be thoroughly researched is thrombocytopenia, which is known to play an important role in activating the immune response to infections. A decrease in platelet count may limit the immune response and consequently increase mortality in patients with pneumonia. The purpose of this study was to investigate whether comorbid thrombocytopenia and pneumonia are associated with poor outcomes. METHODS: This study was a retrospective cohort analysis comparing mortality rates among patients with comorbid thrombocytopenia and pneumonia, pneumonia without thrombocytopenia, and thrombocytopenia without pneumonia. Data were collected from Freeman Health System using International Classification of Diseases, Tenth Revision (ICD-10) codes from January 1, 2019, to December 31, 2021. ICD-10 codes for pneumonia and thrombocytopenia were extracted and stratified into three groups: those with both pneumonia and thrombocytopenia, those with pneumonia without thrombocytopenia, and those with thrombocytopenia without pneumonia. Mortality rates were then compared across the three groups. RESULTS: There were 4,414 patients admitted with pneumonia and 1,157 admissions for thrombocytopenia without pneumonia. Among the 4,414 patients admitted with pneumonia, 3,902 did not have thrombocytopenia, while 512 had thrombocytopenia. Of the patients without thrombocytopenia, 14% (3,902) expired. Among the 512 patients with thrombocytopenia, 43% expired. In the thrombocytopenia without pneumonia group, 11% (1,157) expired. CONCLUSION: These results indicate a significant increase in mortality in patients with both pneumonia and thrombocytopenia compared to those with pneumonia without thrombocytopenia (an increase in mortality of 28.93% with a 95% CI: 24.50-33.36%, P < 0.0001). While pneumonia itself increases mortality compared to the general population, patients with both pneumonia and thrombocytopenia exhibit even higher mortality rates.

Tailoring the Host Range of Ackermannviridae Bacteriophages through Chimeric Tailspike Proteins.

Host range is a major determinant in the industrial utility of a bacteriophage. A model host range permits broad recognition across serovars of a target bacterium while avoiding cross-reactivity with commensal microbiota. Searching for a naturally occurring bacteriophage with ideal host ranges is challenging, time-consuming, and restrictive. To address this, SPTD1.NL, a previously published luciferase reporter bacteriophage for Salmonella, was used to investigate manipulation of host range through receptor-binding protein engineering. Similar to related members of the Ackermannviridae bacteriophage family, SPTD1.NL possessed a receptor-binding protein gene cluster encoding four tailspike proteins, TSP1-4. Investigation of the native gene cluster through chimeric proteins identified TSP3 as the tailspike protein responsible for Salmonella detection. Further analysis of chimeric phages revealed that TSP2 contributed off-target Citrobacter recognition, whereas TSP1 and TSP4 were not essential for activity against any known host. To improve the host range of SPTD1.NL, TSP1 and TSP2 were sequentially replaced with chimeric receptor-binding proteins targeting Salmonella. This engineered construct, called RBP-SPTD1-3, was a superior diagnostic reporter, sensitively detecting additional Salmonella serovars while also demonstrating improved specificity. For industrial applications, bacteriophages of the Ackermannviridae family are thus uniquely versatile and may be engineered with multiple chimeric receptor-binding proteins to achieve a custom-tailored host range.

Development of a Replication-Deficient Bacteriophage Reporter Lacking an Essential Baseplate Wedge Subunit.

Engineered bacteriophages (phages) can be effective diagnostic reporters for detecting a variety of bacterial pathogens. Although a promising biotechnology, the large-scale use of these reporters may result in the unintentional release of genetically modified viruses. In order to limit the potential environmental impact, the ability of these phages to propagate outside the laboratory was targeted. The phage SEA1 has been previously engineered to facilitate food safety as an accurate and sensitive reporter for Salmonella contamination. In this study, homologous recombination was used to replace the expression of an essential baseplate wedge subunit (gp141) in SEA1 with a luciferase, NanoLuc®. This reporter, referred to as SEA1Δgp141.NL, demonstrated a loss of plaque formation and a failure to increase in titer following infection of Salmonella. SEA1Δgp141.NL was thus incapable of producing infectious progeny in the absence of gp141. In contrast, production of high titer stocks was possible when gp141 was artificially supplied in trans during infection. As a reporter, SEA1Δgp141.NL facilitated rapid, sensitive, and robust detection of Salmonella despite an inability to replicate. These results suggest that replication-deficient reporter phages are an effective method to obtain improved containment without sacrificing significant performance or the ease of production associated with many phage-based diagnostic methods.

Isolation and engineering of a Listeria grayi bacteriophage.

The lack of bacteriophages capable of infecting the Listeria species, Listeria grayi, is academically intriguing and presents an obstacle to the development of bacteriophage-based technologies for Listeria. We describe the isolation and engineering of a novel L. grayi bacteriophage, LPJP1, isolated from farm silage. With a genome over 200,000 base pairs, LPJP1 is the first and only reported jumbo bacteriophage infecting the Listeria genus. Similar to other Gram-positive jumbo phages, LPJP1 appeared to contain modified base pairs, which complicated initial attempts to obtain genomic sequence using standard methods. Following successful sequencing with a modified approach, a recombinant of LPJP1 encoding the NanoLuc luciferase was engineered using homologous recombination. This luciferase reporter bacteriophage successfully detected 100 stationary phase colony forming units of both subspecies of L. grayi in four hours. A single log phase colony forming unit was also sufficient for positive detection in the same time period. The recombinant demonstrated complete specificity for this particular Listeria species and did not infect 150 non-L. grayi Listeria strains nor any other bacterial genus. LPJP1 is believed to be the first reported lytic bacteriophage of L. grayi as well as the only jumbo bacteriophage to be successfully engineered into a luciferase reporter.

Validation of the PhageDx™ Listeria Assay for Detection of Listeria Spp. on Stainless Steel and Ceramic Environmental Surfaces AOAC Performance Tested MethodSM 102005.

BACKGROUND: The PhageDx™ Listeria Assay is a simple, specific, and sensitive assay based on the infection of Listeria spp. by selected bacteriophages and the resultant expression of a luciferase reporter gene. Results are generated in as little as 24.5 h for stainless steel and ceramic environmental surfaces. OBJECTIVE: An AOAC Performance Tested MethodsSM (PTM) study was conducted to validate the PhageDx Listeria Assay for the detection of Listeria on stainless steel and ceramic surfaces. METHOD: The performance of the PhageDx method was compared to that of the U.S. Food and Drug Administration (FDA) Bacterial Analytical Manual (BAM) Ch. 10. Inclusivity/exclusivity, product consistency and stability, and robustness testing also were conducted. RESULTS: Inclusivity testing demonstrated that the reporter bacteriophages were specific for Listeria ssp. and detected 58/61 Listeria strains tested, including all 34 L. monocytogenes strains. The reporter bacteriophage also was shown to not detect 46/47 non-Listeria bacteria in exclusivity testing. Robustness testing showed that the method performed well with specific deviations from the standard protocol. Consistency and stability testing demonstrated that the recombinant phage gave consistent results across three production lots and was stable when stored under appropriate conditions for at least 6 months. Matrix studies on stainless steel and ceramic surfaces showed that there was no significant difference between the PhageDx Listeria Assay and the FDA/BAM Chapter 10 reference method. CONCLUSIONS AND HIGHLIGHTS: The validation study demonstrates that the PhageDx Listeria Assay is an effective method for the detection of Listeria spp. on stainless steel and ceramic environmental surfaces and meets the qualifications for AOAC PTM status.

Addressing the Increased Incidence of Common Sexually Transmitted Infections.

Common sexually transmitted infections (STIs) in the United States include genital herpes, HIV, and human papilloma virus. In 2017, the Centers for Disease Control and Prevention released a report detailing a surge in chlamydia, gonorrhea, and syphilis infections in the United States. The authors summarize current trends and discuss epidemiologic factors, disease burden, and patient care. It is important to be aware of the recent increases in these 3 STIs and to be prepared to screen for, diagnose, and manage these infections and their complications.

Using a State Birth Registry as a Quality Improvement Tool.

Background Birth registry data are universally collected, generating large administrative datasets. However, these data are typically not used for quality improvement (QI) initiatives in perinatal medicine because the quality and timeliness of the information is uncertain. Objective We sought to identify and address causes of inaccuracy in recording birth registry information so that birth registry data could support statewide obstetrical quality initiatives in Ohio. Study Design The Ohio Perinatal Quality Collaborative and the Ohio Department of Health Vital Statistics used QI techniques in 15 medium-sized maternity hospitals to identify and remove systemic sources of inaccuracy in birth registry data. The primary outcome was the rate of scheduled deliveries without medical indication between 370/7 and 386/7 weeks at participating hospitals from birth registry data. Results Inaccurate birth registry data most commonly resulted from limited communication between clinical and medical record staff. The rate of scheduled births between 370/7 and 386/7 weeks' gestation without a documented medical indication as recorded in the birth registry declined by 35%. Conclusion A QI initiative aimed at increasing the accuracy of birth registry information demonstrated the utility of these data for surveillance of perinatal outcomes and has led to ongoing efforts to support birth registrars in submitting accurate data.

System for rapid assessment of pneumonia and influenza-related mortality-Ohio, 2009-2010.

Rapid mortality surveillance is critical for state emergency preparedness. To enhance timeliness during the 2009-2010 influenza A H1N1 pandemic, the Ohio Department of Health activated a drop-down menu within Ohio's Electronic Death Registration System for reporting of pneumonia- or influenza-related deaths approximately 5 days postmortem. We used International Classification of Diseases-Tenth Revision (ICD-10) codes, available 2-3 months postmortem as the standard, and assessed their agreement with drop-down-menu codes for pneumonia- or influenza-related deaths. Among 56 660 Ohio deaths during September 2009-March 2010, agreement was 97.9% for pneumonia (κ = 0.85) and 99.9% for influenza (κ = 0.79). Sensitivity was 80.2% for pneumonia and 73.9% for influenza. Drop-down menu coding enhanced timeliness while maintaining high agreement with ICD-10 codes.

Pathways community care coordination in low birth weight prevention.

The evidence is limited on the effectiveness of home visiting care coordination in addressing poor birth outcome, including low birth weight (LBW). The Community Health Access Project (CHAP) utilizes community health workers (CHWs) to identify women at risk of having poor birth outcomes, connect them to health and social services, and track each identified health or social issue to a measurable completion. CHWs are trained individuals from the same highest risk communities. The CHAP Pathways Model is used to track each maternal health and social service need to resolution and CHWs are paid based upon outcomes. We evaluated the impact of the CHAP Pathways program on LBW in an urban Ohio community. Women participating in CHAP and having a live birth in 2001 through 2004 constituted the intervention group. Using birth certificate records, each CHAP birth was matched through propensity score to a control birth from the same census tract and year. Logistic regression was used to examine the association of CHAP participation with LBW while controlling for risk factors for LBW. We identified 115 CHAP clients and 115 control births. Among the intervention group there were seven LBW births (6.1 %) compared with 15 (13.0 %) among non-CHAP clients. The adjusted odds ratio for LBW was 0.35 (95 % confidence interval, 0.12-0.96) among CHAP clients. This study provides evidence that structured community care coordination coupled with tracking and payment for outcomes may reduce LBW birth among high-risk women.

Abdominal and urogenital diseases can often be the cause of lower back pain and sciatic-like symptoms.

SUMMARY The treatment of lower back pain and sciatic-type symptoms are often not related to spinal cord infringement, but are due to other factors such as urogenital irritation and piriformis syndrome. Other factors can exist and it behooves the physician to make a definitive diagnosis in order to prevent treating with medicines and treatments that often do not work. Medicines in high doses can lead to dependence or addiction. A normal MRI test is often a flag to the physician that something other than spinal problems may be the cause. A complete workup must be performed including imaging procedures, diagnostic testing and specialized physical examinations if initial diagnosis and treatments do not produce an amelioration of symptoms. There are many causes of chronic lower back pain and sciatica-type symptoms and if the problems and symptoms persist, they should be investigated.

De novo pudendal neuropathy after TOT-O surgery for stress urinary incontinence.

BACKGROUND AND OBJECTIVES: Five cases of pelvic nerve complications after transobturator tape (TOT) inside-out surgical procedures for stress urinary incontinence are presented. METHODS: We conducted a chart review of patients with complications referred to our practice. RESULTS: Five patients with nerve complications after TOT inside-out procedures were investigated. Pudendal neuropathy and interstitial cystitis were seen in this series of patients with several patients having myofascial pain in the lower abdominal area. CONCLUSIONS: Although not commonly reported, complications from needle placement and from the area of needle exit in a TOT procedure can exist, and the surgeon must be careful when placing the needle through the area of the obturator fossa.

Anterior vaginal wall tenderness (AVWT) as a physical symptom in chronic pelvic pain.

BACKGROUND AND OBJECTIVES: Chronic pelvic pain is often difficult to diagnose and treat properly. Physicians called on to treat this problem may not be able to give a specific diagnosis. The aim of this study was to see whether the physical presence of anterior vaginal wall tenderness could help narrow down and elucidate diagnoses in a practice focusing on diagnosis and treatment of chronic pelvic pain. METHODS: The study cohort comprised 284 patients with chronic pelvic pain limited to gynecologic and lower urinary problems. Histories, physical examinations, and endoscopic procedures were performed on each patient. An analysis of this information was conducted. RESULTS: Of the chronic pelvic pain patients, 78% had endometriosis, 81% had interstitial cystitis, and 61% had both concurrently. The sensitivity of anterior vaginal wall tenderness (AVWT) in patients with interstitial cystitis was 95%, and in those with only endometriosis and no interstitial cystitis, the sensitivity was 17%. The positive predictive value for interstitial cystitis was 85%, and for endometriosis it was 67%. CONCLUSIONS: Examination of the anterior vaginal wall with an empty bladder at the initial examination can lead one to suspect interstitial cystitis and possibly either concomitant or singular endometriosis and allow the physician to approach the workup accordingly.

Infant death among Ohio resident infants born at 32 to 41 weeks of gestation.

OBJECTIVE: The aim of this study was to determine gestational age-specific, adjusted infant mortality rates for Ohio. STUDY DESIGN: Using a retrospective cohort design, all births and infant deaths from 2003-2005 were included in multivariable regression analyses. Variations in cause and timing of infant death were determined. RESULTS: Compared with births at 39 or 40 weeks, adjusted likelihood of infant death increased progressively between 38-32 weeks' gestational age. At later gestational ages, death was more likely caused by sudden infant death syndrome or intentional injury compared with congenital malformations and asphyxia or cerebral palsy at earlier gestational ages. Less mature infants tended to die earlier. CONCLUSION: The current study confirms for Ohio and extends the findings of others that infant mortality risk is increased for births at late preterm and near-term gestational ages. Decisions to deliver before 39 weeks should consider increased likelihood of infant death that may be unrelated to fetal malformations or maternal illness.

Evidence of methamphetamine exposure in children removed from clandestine methamphetamine laboratories.

OBJECTIVE: To determine whether asymptomatic children removed from clandestine methamphetamine laboratories have evidence of exposure to methamphetamine. METHODS: Retrospective chart review of children removed from law enforcement-certified clandestine methamphetamine laboratories in the Tulsa area of Oklahoma and Sacramento County, California. Exposure was determined by positive urine toxicology for methamphetamine. RESULTS: One hundred four children were evaluated after removal from clandestine methamphetamine laboratories. Forty-eight children (46%) tested positive for methamphetamine. Timed urine results were known for 68 of 104, with no child testing positive after 6.5 hours from being removed from the laboratory. No child required emergency medical treatment at the time urine samples were obtained. CONCLUSIONS: Almost half of the children in this sample had evidence of exposure to methamphetamine soon after removal from methamphetamine manufacturing environments. Further research is indicated to determine the health effects of subclinical methamphetamine exposure.

Clostridium difficile infection in Ohio hospitals and nursing homes during 2006.

CONTEXT: Healthcare data suggest that the incidence and severity of Clostridium difficile infection (CDI) in hospitals are increasing. However, the overall burden of disease and the mortality rate associated with CDI, including the contribution from cases of infection that occur in nursing homes, are poorly understood. OBJECTIVE: To describe the epidemiology, disease burden, and mortality rate of healthcare-onset CDI. METHODS: In 2006, active public reporting of healthcare-onset CDI, using standardized case definitions, was mandated for all Ohio hospitals and nursing homes. Incidence rates were determined and stratified according to healthcare facility characteristics. Death certificates that listed CDI were analyzed for trends. RESULTS: There were 14,329 CDI cases reported, including 6,376 cases at 210 hospitals (5,217 initial cases [ie, cases identified more than 48 hours after admission to a healthcare facility in patients who had not had CDI during the previous 6 months] and 1,159 recurrent cases [ie, cases involving patients who had had CDI during the previous 6 months]) and 7,953 cases at 955 nursing homes (4,880 initial and 3,073 recurrent cases) . After adjusting for missing data, the estimated total was 18,200 cases of CDI, which included 7,000 hospital cases (5,700 initial and 1,300 recurrent cases) and 11,200 nursing homes cases (6,900 initial and 4,300 recurrent cases). The rate for initial cases was 6.4-7.9 cases/10,000 patient-days for hospitals and 1.7-2.9 cases/10,000 patient-days for nursing homes. The rate for initial cases in nursing homes decreased during the study (P < .001). Nonpediatric hospital status (P = .011), a smaller number of beds (P = .003), and location in the eastern or northeastern region of the state (P = .011) were each independently associated with a higher rate of initial cases in hospitals. Death certificates for 2006 listed CDI among the causes of death for 893 Ohio residents; between 2000 and 2006, this number increased more than 4-fold. CONCLUSION: Healthcare-onset CDI represents a major public health threat that, when considered in the context of an increasing mortality rate, should justify a major focus on prevention efforts.

Correlation of anterior vaginal wall pain with endometriosis in infertile patients.

OBJECTIVE: To investigate whether anterior vaginal wall tenderness in a patient with unexplained infertility correlated to a high percentage of finding endometriosis on laparoscopy. METHOD: Fifty-five consecutive patients with unexplained infertility had vaginal examinations with anterior wall palpation to determine whether there was tenderness (AVWT). As part of the infertility workup, laparoscopy, biopsies and cystoscopy with hydrodistention were performed. RESULTS: The prevalence ofendometriosis in this study was 78%. The sensitivity of positive AVWT on palpation with patients who were found to have endometriosis was 84%, and the specificity was 75%. The positive predictive value was 86% and the negative predictive value was 69%. CONCLUSION: Unexplained infertility may be amenable to treatment in finding problems such as endometriosis, adhesions or subtle other problems that can be corrected by use of laparoscopy instead of going directly to in vitro fertilization. AVWT is a test that may be able to aid physicians in choosing a management to treat a patient with a laparoscopy early in the workup.

Utilizing the great blue heron (Ardea herodias) in ecological risk assessments of bioaccumulative contaminants.

Selection of an appropriate species is a key element of effective ecological risk assessments (ERA), especially when site-specific field studies are to be employed. Great blue herons (GBH) possess several ideal characteristics of a receptor species for the assessment of bioaccumulative compounds in the environment, such as ease of study, high potential for exposure, widespread distribution, and territorial foraging behavior. Methodologies for assessing exposure and population health are described herein. As outlined, the collection of GBH eggs, GBH nestling blood, and adult GBH blood allows for the determination of contaminant concentrations in various GBH tissues, a top-down assessment, which can be done in conjunction with predicted dietary exposure, a bottom-up assessment, to support a multiple lines of evidence approach. Additionally, population parameters, such as productivity and survival, can also be measured to elucidate if the contaminant exposure may be causing population level effects. Over the course of two years, three GBH rookeries were monitored for productivity and nestling exposure. Nests were monitored from blinds and individually accessed at multiple time points to obtain measures of nestling health, band nestlings, and collect eggs and nestling plasma. Multiple nests could frequently be accessed by climbing one tree, resulting in minimal effort to obtain the necessary sample size. Additionally, 51 adult GBH, captured in their foraging areas, were banded, and provided a blood sample. With these samples, a statistical difference in tissue based exposure was identified between the reference and target area. Statistically significant differences were also identified between the upper and lower reaches of the target area, thereby identifying a range of doses geographically which could be correlated to specific measurement endpoints. The ability to identify a dose response greatly increases the ability of the dataset to determine causation, a key goal of such studies. Overall, the use of the described methods allowed for the collection of a statistically sufficient and ecologically relevant dataset with reasonable effort and minimal impact on GBH.

The relationship between interstitial cystitis and endometriosis in patients with chronic pelvic pain.

OBJECTIVE: This study was designed to determine the relationship between interstitial cystitis (IC), endometriosis (endo), and chronic pelvic pain (CPP) in individuals in whom nongynecological and nonurological problems had been previously ruled out. METHODS: A prospective study of 162 consecutive women with a complaint of chronic pelvic pain seen in the clinic was performed between August 2002 and December 2005. These patients underwent a workup to exclude other causes of pelvic pain, had PUF (Pain Urgency and Frequency) questionnaires filled out, and underwent a laparoscopy and a cystoscopy with hydrodistention. Pain levels were determined, and treatment was reviewed and enumerated. Results were obtained and quantified. RESULTS: In this study, 123 (76%) patients were diagnosed with active endometriosis, 133 (82%) were diagnosed with interstitial cystitis, and 107 (66%) had both disease entities simultaneously. Thirteen (8%) patients were diagnosed with pathologies unrelated to endometriosis and interstitial cystitis. Pain levels were seen to decrease at 6 months in all groups of patients with the exception of those patients with endometriosis only. CONCLUSION: CPP is a difficult, taxing, and frustrating concern for many women in the United States. These individuals have traditionally been difficult to treat. A large number of women with CPP in our patient population have been shown to have endometriosis, interstitial cystitis, or both. Therefore, a workup for premenopausal individuals with CPP involves obtaining a history that keys into possible nongynecologic causes of pain, a complete accounting of urinary problems, and a thorough history of gynecological problems. A physical examination with a comprehensive history should be performed, and the investigation may include the possibility of a simultaneous laparoscopy and cystoscopy if warranted. These procedures can serve as both a means for diagnosis and treatment of these problems when encountered.

The treatment of mild endometriosis with laser laparoscopy: a two-step treatment analysis of patients whose primary therapy was successful.

OBJECTIVES: The most advantageous treatment for pelvic endometriosis that is not extensive has long been the subject of debate. In recent years, the ability to detect atypical presentations has allowed the gynecological surgeon to treat this entity more readily. The treatment in the past has been concerned with the singular treatment being applied at the time, not on the prior treatment effects on current therapy. The purpose of the current study was to see whether previous successful treatment modalities affected the success of subsequent laparoscopic laser fulguration treatment of endometriosis. METHODS: Patients who were previously treated for their endometriosis (minimal and mild) and had success in achieving pregnancy were treated for their disease after failing to become pregnant after delivery. They were treated with laparoscopic laser fulguration of the disease and the results were examined by chi-square (chi2) analysis. RESULTS: There appears to be no difference in current pregnancy rates in patients who were successfully treated in the original treatment for endometriosis, no matter which of the therapies had been used. CONCLUSION: If endometriosis is diagnosed at the time of laparoscopy and is easily amenable to treatment, it should be treated at the time of surgery regardless of prior treatment and results.

Chronic pelvic pain: the occurrence of interstitial cystitis in a gynecological population.

OBJECTIVE: The objective of this study was to determine what relationship exists between interstitial cystitis and chronic pelvic pain in patients. METHODS: A prospective study of 35 women with a complaint of chronic pelvic pain was performed between August 2002 and September 2003. These patients underwent a workup to exclude other causes of pelvic pain and underwent a laparoscopy and a cystoscopy with hydrodistention at 80 cm of hydrostatic water pressure. Results were obtained and quantified. RESULTS: Twenty-eight patients (80%) were diagnosed with interstitial cystitis, 28 were diagnosed with endometriosis (80%), 24 had both disease entities simultaneously (69%), and 32 (91%) had endometriosis, interstitial cystitis, or both. Three patients (9%) had neither and were diagnosed with other pathologies. CONCLUSIONS: Chronic pelvic pain is a major concern for many women in the United States. Patients with chronic pelvic pain have traditionally been difficult to manage. A large percentage of women presenting with chronic pelvic pain have been shown to have endometriosis, interstitial cystitis, or both. Therefore, an appropriate workup for those individuals with chronic pelvic pain involves not only obtaining a good history and performing a good physical examination, but the possibility of a cystoscopy being performed when a laparoscopy has been deemed necessary for diagnosis of the pain. These procedures can serve as both a means for diagnosis and short-term treatment of these problems when encountered.