e-Health for COVID-19 Epidemic: The Arizona Poison and Drug Information Center Experience.

Background: A significant challenge of the COVID-19 epidemic was the dissemination of accurate and timely information to the public, health care providers, and first responders. We describe the expansion of the Arizona Poison and Drug Information Center (APDIC) to fill such a need for residents of Arizona. Methodology: The original mission of the APDIC was recognition and management of chemical exposure, poisoning, envenomation, and drug-related medical problems. In response to COVID-19, APDIC expanded its personnel and facilities to accommodate telephone calls and teleconsults regarding COVID-19. Thirteen different topics dealing with COVID-19 were addressed and tracked and included: testing information, isolation, prevention, personal protective equipment, travel, vaccines, therapies, antibody testing, contact tracing, exposure to the virus and what to do in businesses, at work or at school regarding isolation and quarantine. Results: Responding to the public health needs, APDIC accepted >320,000 telephone calls and completed 48,346 teleconsults from March 3, 2020 to March 3, 2021. This represented a 15-fold increase in calls and twice the number of consults over 2019. Upon release of the vaccine, calls increased sharply with >7,000 calls in 1 day (February 7, 2021). Conclusion: In conclusion, the APDIC, rapidly expanded to address urgent public health information needs surrounding COVID-19 while still accomplishing its founding mission.

Use of Crotalidae equine immune F(ab')2 antivenom for treatment of an Agkistrodon envenomation.

INTRODUCTION: Anavip (F(ab')2AV) is a lyophilized F(ab')2 immunoglobulin fragment derived from horses immunized with venom from Bothrops asper and Crotalus durissus. It was approved by the FDA in 2015 for treatment of North American rattlesnake envenomation but not for Agkistrodon envenomation. Published data regarding the efficacy and safety of Anavip in treating Agkistrodon envenomations is limited. We present a case of a patient treated with Anavip after confirmed Agkistrodon laticinctus envenomation. CASE DETAILS: A 77 year-old man was bitten on his fifth finger by a captive A. laticinctus. He was taken to a local emergency department where he received a 10 vial initial dose of F(ab')2AV for pain and swelling and was transferred. At the receiving facility, his pain had improved and his swelling had not progressed. Over the next 30 h, his platelets declined to 132,000/mm3 and he received an additional 4 vials of F(ab')2AV. The remainder of his course was unremarkable with complete recovery by 3 months. DISCUSSION: This case provides an additional published datapoint on the use of this F(ab')2AV in the treatment of envenomation by Agkistrodon.

Scorpion Stings and Antivenom Use in Arizona.

BACKGROUND: Arizona's rugged desert landscape harbors many venomous animals, including a small nocturnal scorpion, Centruroides sculpturatus, whose venom can cause severe neuromotor disturbance. An effective antivenom is available at selected health care facilities in the state. METHODS: We analyzed 4398 calls of scorpion stings to the Arizona Poison and Drug Information Center (APDIC) in Tucson over a period of 3 years, from January 2017 to December 2019. RESULTS: We followed 1952 (44.4%) of the victims to resolution. We excluded 2253 callers with minimal effects of the sting and 193 victims with possible toxic effects who were lost to follow-up. The most common complaints among callers were pain at the sting site in 88.9% and local numbness in 62.2%. Detailed clinical information was obtained from 593 calls from a health care facility. Neuromotor signs consistent with C. sculpuratus envenomation included nystagmus in 163 (27.5%), hypersalivation in 91 (15.3%), and fasciculations in 88 (14.8%). Antivenom (Anascorp; Rare Disease Therapeutics, Inc., Franklin, Tenn) was administered to 145 patients. Most were children <5 years old (n = 76, or 54.4%); 27 (18.6%) were 5-9 years old and 42 (30.0%) were ≥10 years of age. About half, 79 of 145 (54.5%) victims who received antivenom, met the APDIC recommended use criteria. CONCLUSIONS: Patients treated with antivenom exhibited a rapid resolution of symptoms without immediate or delayed hypersensitivity reactions. We recommend broadened availability of antivenom at sites where it is most needed.

Honeybee Stings in the Era of Killer Bees: Anaphylaxis and Toxic Envenomation.

BACKGROUND: Twenty-six years after the arrival of "killer bees" in Arizona, the entire state with the exception of high elevations in the north is populated with this bee variety and 11 people have died at the scene of massive bee attacks. METHODS: Because of the aggressive behavior of these bees we studied bee stings reported to the Arizona Poison and Drug Information Center. The center received 399 calls regarding 312 victims of bee stings from January 2017 to June 2019. Calls originated from private residences and emergency centers. RESULTS: Stings occurred at victims' home residences in 272 (84.7%) of cases and 24 (7.5%) in public areas; 251 people suffered 1 sting; 42 individuals, 2-10 stings, 4 had 11-49 stings, and 13 individuals had >50 stings (so-called massive stinging). Three individuals were admitted to intensive care units (ICU) and one 35-year-old man died of anaphylaxis after 1 sting; moderate clinical effects occurred in 32 individuals including 6 admitted to the hospital but not in the intensive care unit. Anaphylaxis occurred in 30 (9.6%) of individuals, 16 receiving 1 sting. Toxic effects, tachycardia, elevated creatinine, or rhabdomyolysis occurred in 13 (4.2%) individuals. CONCLUSIONS: In the past, individuals stung more than 50 times were beekeepers working with European honeybees, whereas, in the current era, single as well as massive stings are the result of feral "killer bees." This change in epidemiology requires a new approach to sting victims: those with massive stinging should be evaluated and observed for anaphylaxis and serial laboratory values obtained for days to detect the toxic effects of envenomation.

Warnings for drug-drug interactions in consumer medication information provided by community pharmacies.

OBJECTIVES: In 2006, the U.S. Food and Drug Administration (FDA) issued a draft guidance for pharmacies to provide consumer medication information (CMI) to patients receiving prescription medications. The objective of this study was to evaluate CMI leaflets provided by community pharmacies for accuracy and completeness regarding drug-drug interactions (DDIs). METHODS: CMI leaflets were obtained for 3 commonly prescribed medications (azithromycin, ciprofloxacin, and simvastatin) from 14 community pharmacies that are part of 6 chain organizations that operate in southern Arizona. Three to 4 salient interacting medications for each leaflet medication were identified with the use of 2 well recognized drug compendia. The content of the DDI information in the leaflets was evaluated for completeness. The font size and reading level of each leaflet were assessed as well. RESULTS: The CMI provided by 14 pharmacies appeared to be produced by 2 information vendors, Wolters Kluwer and First Databank. This was evident based on the identical wording and attribution (e.g., copyright statements) on the leaflets. The CMI from First Databank mentioned 5 of the 11 previously identified interactions with the target medications, although 1 chain in this group chose not to print the DDI section at all and as a result scored 0. The CMI developed by Wolters Kluwer mentioned only 2 of the 11 identified DDIs. The average reading grade level for First Databank leaflets was 10.6 (SD 2.87), and the reading level for the CMI from Wolters Kluwer was 5.0 (SD 1.02). The font sizes varied from 8 to 12 points; FDA recommends that the information be printed in 12-point size or larger. CONCLUSION: Community pharmacies appear to be distributing CMI leaflets with limited warnings about serious and well known DDIs. The results of this study suggest that consumers are not being informed through the CMI about important known DDIs.

Prophylactic Antibiotics Are Not Needed Following Rattlesnake Bites.

BACKGROUND: Antibiotics are sometimes administered to victims of rattlesnake bites in the hope of preventing infections. Experts in the field recommend that prophylactic antibiotics not be used because secondary infections are rare. Current recommendations are based on a small number of studies conducted in the United States. We decided to reexamine the issue by taking advantage of a large database on snakebites in Arizona. This allowed us to determine how often prophylactic antibiotics were used and whether or not they were effective. METHODS: We obtained data from the Arizona Poison and Drug Information Center electronic medical record, Toxicall. Rattlesnake bites occurring over 18 years (1999-2016) were analyzed according to the descriptors: infection, pus, isolation of bacteria, and antibiotic use. RESULTS: There were 2748 evaluable patients identified as having rattlesnake bites. The mean number of bite victims was 153 per year. Most (72%) were male. Their ages ranged from 8 months to 91 years. Prophylactic antibiotics were administered to 120 of 2748 (4.4%) victims. There were 27 postbite infections (0.98%) but no deaths. Victims sometimes manipulated the wound sites. Microorganisms were isolated from only 9 patients. Only a Salmonella sp. was of certain reptilian origin; the others were likely of human origin. CONCLUSIONS: This large study supports recommendations that prophylactic antibiotics not be used following rattlesnake bites in the United States. The incidence of postbite infections was low, <1%. All but 1 of the bacteria isolated from the wounds were common inhabitants of human skin and not found in oral secretions of rattlesnakes.

Intentional use of carbapenem antibiotics for valproic acid toxicity: A case report.

WHAT IS KNOWN AND OBJECTIVE: The interaction between valproic acid (VPA) and carbapenem antibiotics is well described with previous reports suggesting a reduction in VPA half-life between 47% and 90%. As described in this case, this interaction might be beneficial in the setting of toxic VPA ingestion. CASE DESCRIPTION: An intubated, unresponsive patient arrived via emergency medical services after toxic VPA ingestion. Meropenem was prescribed for a suspected pneumonia and to take advantage of the VPA interaction. We observed a 56% decline in half-life with short-term meropenem dosing and an improvement in mental status shortly after administration. WHAT IS NEW AND CONCLUSION: Our findings suggest a potential role for short-term carbapenem therapy for VPA overdose.

Centruroides sculpturatus envenomation in three adult patients requiring treatment with antivenom.

CONTEXT: Envenomation by Centruroides sculpturatus can manifest with cranial nerve dysfunction and neuromuscular hyperactivity. While these symptoms are most commonly seen in young children, they may also be seen in adults. CASE DETAILS: Three cases of adult patients are presented with grades III & IV scorpion envenomation. They reported symptoms including disconjugate, roving eye movements, and motor involvement. Also reported were hyposmia, difficulty with fine motor movements, and dysgeusia. All were first treated with benzodiazepines with little to no effect. They then received a three vial antivenom bolus with resolution of severe symptoms within 30-60 min. DISCUSSION: Severe Centruroides envenomation can occur in adults as well as children. These three cases demonstrate the usefulness, safety, and effectiveness of antivenom therapy to quickly relieve symptoms in adult patients with grades III & IV envenomations.

Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disease, characterised by hypogammaglobulinaemia leading to recurrent infections and various complications. The aim of this study was to classify CVID patients based on four known classifications (Paris, Freiburg, EUROclass, and B-cell patterns) by measurement of B-cell subsets and to assess the relation of each classification with clinical manifestations. METHODS: We measured all B-cell subsets as both absolute count and percentage in 30 CVID patients and 30 healthy individuals using four-colour flow cytometry. Moreover, we evaluated antibody responses to pneumococcal vaccine in patients. RESULTS: A significant reduction in percentage of terminal B-cell subsets (total, marginal zone-like, switched memory, IgM-only memory, total memory B-cells and plasmablast) and absolute count of all B-cell subsets along with a strong increase in CD21low B-cells has been observed in patients. Patients with splenomegaly and hepatomegaly clustered in group Ia, smB+21low and group 1 based on known classifications, and significantly tended to have a decreased transitional and marginal zone-like B-cells count, as well as an increase in CD21low B-cell counts. Patients with lymphadenopathy, bronchiectasis and allergy had a significant decrease in absolute count of total memory, switched memory and total B-cells, respectively. CONCLUSION: Classification of patients could provide useful information to guide clinicians in long-term follow-up of CVID patients. Our data demonstrate that it may be more accurate to use absolute counts of B-cell subpopulations in CVID patients because absolute counts of B-cell subsets are more associated with clinical manifestations compared with their percentage and also four known classifications

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Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disease, characterised by hypogammaglobulinaemia leading to recurrent infections and various complications. The aim of this study was to classify CVID patients based on four known classifications (Paris, Freiburg, EUROclass, and B-cell patterns) by measurement of B-cell subsets and to assess the relation of each classification with clinical manifestations. METHODS: We measured all B-cell subsets as both absolute count and percentage in 30 CVID patients and 30 healthy individuals using four-colour flow cytometry. Moreover, we evaluated antibody responses to pneumococcal vaccine in patients. RESULTS: A significant reduction in percentage of terminal B-cell subsets (total, marginal zone-like, switched memory, IgM-only memory, total memory B-cells and plasmablast) and absolute count of all B-cell subsets along with a strong increase in CD21low B-cells has been observed in patients. Patients with splenomegaly and hepatomegaly clustered in group Ia, smB+21low and group 1 based on known classifications, and significantly tended to have a decreased transitional and marginal zone-like B-cells count, as well as an increase in CD21low B-cell counts. Patients with lymphadenopathy, bronchiectasis and allergy had a significant decrease in absolute count of total memory, switched memory and total B-cells, respectively. CONCLUSION: Classification of patients could provide useful information to guide clinicians in long-term follow-up of CVID patients. Our data demonstrate that it may be more accurate to use absolute counts of B-cell subpopulations in CVID patients because absolute counts of B-cell subsets are more associated with clinical manifestations compared with their percentage and also four known classifications.

Kissing Bug (Triatoma spp.) Intrusion into Homes: Troublesome Bites and Domiciliation.

Kissing bugs (Triatoma spp.) frequently enter homes and bite human and pet occupants. Bites may lead to severe allergic reactions and, in some cases, death. Kissing bugs are also vectors of Trypanosoma cruzi, the cause of Chagas disease. In general, modern houses in the United States are not conducive to domiciliation of kissing bugs (bugs living out their entire life within the home with the presence of eggs, nymphs, adults, and exuviae). Construction features such as concrete foundations, solid walls and ceilings, window screens, tight thresholds for doors and windows, and other measures impede bug entry into homes, and air conditioning reduces the need for open doors and windows. Where Chagas disease is endemic in Mexico and Central and South America, homes often have thatch roofs, adobe walls, and open doors and windows. We investigated numerous instances of kissing bug intrusions into homes in Southern Arizona, California, and Louisiana and documented the reactions to kissing bug bites. Our work confirms the importance of modern home construction in limiting kissing bug intrusions. Older homes, especially those lacking modern screening, caulking, and weather stripping to reduce air leakage, may be subject to kissing bug intrusions and domiciliation. We describe a community in Southern Arizona where domiciliation of homes by Triatoma recurva is common. We also provide recent data regarding kissing bug bites and allergic reactions to the bites.

Micafungin triggers caspase-dependent apoptosis in Candida albicans and Candida parapsilosis biofilms, including caspofungin non-susceptible isolates.

Candida biofilms play an important role in infections associated with medical devices and are resistant to antifungals. We hypothesized that the echinocandin micafungin (MICA) exerts an enhanced antifungal activity against caspofungin (CAS)-susceptible (CAS-S) and CAS-non-susceptible (CAS-NS) Candida albicans and Candida parapsilosis which is at least in part through apoptosis, even in the biofilm environment. Apoptosis was characterized by detecting reactive oxygen species (ROS) accumulation, depolarization of mitochondrial membrane potential (MMP), DNA fragmentation, lack of plasma membrane integrity, and metacaspase activation following exposure of Candida biofilm to MICA for 3h at 37°C in RPMI 1640 medium. The minimum inhibitory concentration was higher for CAS (2.0-16.0 µg/mL) than for MICA (1.0-8.0 µg/mL) for Candida biofilms. Elevated intracellular ROS levels and depolarization of MMP was evident in CAS-S C. albicans (3.0-4.2 fold) and C. parapsilosis (4.8-5.4 fold) biofilms compared with CAS-NS (1.2 fold) after exposure to MICA (0.25x-1xMIC). Elevated intracellular ROS levels and depolarization of MMP was evident in CAS-S C. albicans (3.0-4.2 fold) and C. parapsilosis (4.8-5.4 fold) biofilms compared with CAS-NS (1.2 fold) after exposure to MICA (0.25x-1xMIC). Finally higher ß-1, 3 glucan levels were seen in sessile cells compared to planktonic cells, especially in CAS-NS strains. MICA treatment might induce a metacaspase-dependent apoptotic process in biofilms of both CAS-S C. albicans and C. parapsilosis, and to some degree in CAS-NS strains.

Glucocorticosteroids do not impact directly growth rate and biomass of Rhizopus arrhizus (syn. R. oryzae) in vitro.

Glucocorticoid (GC) use is a common risk factor for invasive fungal infections. This is attributed to the complex dysregulation of immunity caused by GCs. However, studies have demonstrated increased growth with GC exposure for some molds, such as Aspergillus fumigatus and Exserohilum rostratum. No such data exist for Mucorales. Therefore, we investigated the influence of GC exposure on the growth of Rhizopus arrhizus (syn. R. oryzae) in different culture media and in different atmospheres. We measured continuous spore growth using spectrophotometry and biomass variations using XTT assay. We did not observe enhanced growth or biomass variation with any of the GCs regardless of the medium or conditions. These results support the existence of fungus-specific differences in the effect of GCs on fungal biology.

Possible mechanism of antifungal phenazine-1-carboxamide from Pseudomonas sp. against dimorphic fungi Benjaminiella poitrasii and human pathogen Candida albicans.

AIM: Investigation of antifungal mechanism of phenazine 1-carboxamide (PC) produced by a Pseudomonas strain MCC2142. METHODS AND RESULTS: An antifungal metabolite produced by a Pseudomonas was purified and identified as PC. Human pathogenic fungi such as Candida albicans, Candida glabrata, Cryptococcus neoformans, Fusarium oxysporum, Aspergillus fumigatus and Aspergillus niger were found to be inhibited by PC (MIC90 32-64 µg ml(-1)). Addition of PC (20 µg ml(-1)) during yeast (Y)-hypha (H) transitions inhibited germ tube formation by >90% and >99% in C. albicans National Collection of Industrial Microorganisms (NCIM) 3471 and nonpathogenic model Benjaminiella poitrasii, respectively. After exposure to PC (20 µg ml(-1)), 75-80% yeast cells of B. poitrasii and C. albicans NCIM 3471 showed rhodamine 123 fluorescence indicating high intracellular reactive oxygen species (ROS) production. ROS further led to hyperpolarization of mitochondrial membrane, subsequently induction of apoptosis as evident by externalization of phosphatidylserine, DNA fragmentation, chromatin condensation and finally death in B. poitrasii. In C. albicans NCIM 3471, PC (20 µg ml(-1)) induced apoptosis. CONCLUSIONS: The antifungal effect of PC in B. poitrasii and C. albicans may be due to ROS-mediated apoptotic death. SIGNIFICANCE AND IMPACT OF THE STUDY: Inhibition of Y-H transition of B. poitrasii and C. albicans by PC indicates that it may prove useful in the control of dimorphic human pathogens.

Mechanical and physical properties of calcium silicate/alumina composite for biomedical engineering applications.

The focus of this study is to investigate the effect of Al2O3 on α-calcium silicate (α-CaSiO3) ceramic. α-CaSiO3 was synthesized from CaO and SiO2 using mechanochemical method followed by calcinations at 1000°C. α-CaSiO3 and alumina were grinded using ball mill to create mixtures, containing 0-50w% of Al2O3 loadings. The powders were uniaxially pressed and followed by cold isostatic pressing (CIP) in order to achieve greater uniformity of compaction and to increase the shape capability. Afterward, the compaction was sintered in a resistive element furnace at both 1150°C and 1250°C with a 5h holding time. It was found that alumina reacted with α-CaSiO3 and formed alumina-rich calcium aluminates after sintering. An addition of 15wt% of Al2O3 powder at 1250°C were found to improve the hardness and fracture toughness of the calcium silicate. It was also observed that the average grain sizes of α-CaSiO3 /Al2O3 composite were maintained 500-700nm after sintering process.

In vitro characterization and mechanical properties of ß-calcium silicate/POC composite as a bone fixation device.

Calcium silicate (CS, CaSiO3 ) is a bioactive, degradable, and biocompatible ceramic and has been considered for its potential in the field of orthopedic surgery. The objective of this study is the fabrication and characterization of the ß-CS/poly(1.8-octanediol citrate) (POC) biocomposite, with the goals of controlling its weight loss and improving its biological and mechanical properties. POC is one of the most biocompatible polymers, and it is widely used in biomedical engineering applications. The degradation and bioactivity of the composites were determined by soaking the composites in phosphate-buffered saline and simulated body fluid, respectively. Human osteoblast cells were cultured on the composites to determine their cell proliferation and adhesion. The results illustrated that the flexural and compressive strengths were significantly enhanced by a modification of 40% POC. It was also concluded that the degradation bioactivity and amelioration of cell proliferation increased significantly with an increasing ß-CS content.

The calcineurin pathway inhibitor tacrolimus enhances the in vitro activity of azoles against Mucorales via apoptosis.

The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant Mucorales. We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37°C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca(2+), phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome c release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 µg/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 µg/ml) for Rhizopus oryzae, Cunninghamella bertholletiae, and Mucor circinelloides. Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of R. oryzae (10 to 50%), C. bertholletiae (5 to 50%), and M. circinelloides (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca(2+) and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders Mucorales sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies.

Detailed investigations on the solid cell culture and antimicrobial activities of the Iranian Arnebia euchroma.

In pursuit of strong shikalkin-producing cell lines, seeds of the Iranian Arnebia euchroma were collected from Dena altitudes in the central Zagross. Chemical analysis showed that the dried root of the plant contained about 8.5% (w/w) shikalkin pigment. The root explants of the young plantlets, obtained from the germinated seeds, were used for establishing callus. Then, parameters effective on proliferation and pigment production of the resulting calli were studied in detail. Accordingly, two modified media called mLS and mM9 were optimized for propagation and pigment production, respectively. Using these media, the biomass of the A. euchroma calli was increased to 600%, and the pigment production reached to a maximum of 16.3 mg per gram of the wet biomass in a period of a subculture (21 days). Parallel to these experiments, the antimicrobial activity of shikalkin pigment was examined on some fungi and gram-positive and gram-negative bacteria. Results indicated that the pigment was almost ineffective on fungi and gram-negative bacteria, but it was meaningfully effective against Micrococcus luteus.