Rate of COVID-19 vaccination among patients with cancer who tested positive for severe acute respiratory syndrome-coronavirus 2: Analysis of the American Society of Clinical Oncology Registry.

BACKGROUND: The availability of safe and effective COVID-19 vaccines has enabled protections against serious COVID-19 outcomes, which are particularly important for patients with cancer. The American Society of Clinical Oncology Registry enabled the study of COVID-19 vaccine uptake in patients with cancer who were positive for severe acute respiratory syndrome-coronavirus 2. METHODS: Medical oncology practices entered data on patients who were in cancer treatment. The cohort included patients who had severe acute respiratory syndrome-coronavirus 2 infection in 2020 and had visits and vaccine data after December 31, 2020. The primary end point was the time to first vaccination from January 1, 2021. Cumulative incidence estimates and Cox regression with death as a competing risk were used to describe the time to vaccine uptake and factors associated with vaccine receipt. RESULTS: The cohort included 1155 patients from 56 practices. Among 690 patients who received the first vaccine dose, 92% received the second dose. The median time to vaccine was 99 days. After adjustment, older patients were associated with a higher likelihood of vaccination compared with patients younger than 50 years in January through March 2021, and age exhibited a linear effect, with older patients showing higher rates of vaccination. Metastatic solid tumors (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73-0.98) or non-B-cell hematologic malignancies (HR, 0.71; 95% CI, 0.54-0.93) compared with nonmetastatic solid tumors, and any comorbidity (HR, 0.83; 95% CI, 0.73-0.95) compared with no comorbidity, were associated with lower vaccination rates. Area-level social determinants of health (lower education attainment and higher unemployment rates) were associated with lower vaccination rates. CONCLUSIONS: Patient age, cancer type, comorbidity, area-level education attainment, and unemployment rates were associated with differential vaccine uptake rates. These findings should inform strategies to communicate about vaccine safety and efficacy to patients with cancer.

Synthesis and in vitro antiprotozoal evaluation of novel metronidazole-Schiff base hybrids.

Herein we report the synthesis of 21 novel small molecules inspired by metronidazole and Schiff base compounds. The compounds were evaluated against Trichomonas vaginalis and cross-screened against other pathogenic protozoans of clinical relevance. Most of these compounds were potent against T. vaginalis, exhibiting IC50 values < 5 µM. Compound 20, the most active compound against T. vaginalis, exhibited an IC50 value of 3.4 µM. A few compounds also exhibited activity against Plasmodium falciparum and Trypanosomal brucei brucei, with compound 6 exhibiting an IC50 value of 0.7 µM against P. falciparum and compound 22 exhibiting an IC50 value of 1.4 µM against T.b. brucei. Compound 22 is a broad-spectrum antiprotozoal agent, showing activities against all three pathogenic protozoans under investigation.

The Inhibitory Activity of Anthraquinones against Pathogenic Protozoa, Bacteria, and Fungi and the Relationship to Structure.

Plant-derived anthraquinones were evaluated in cell assays for their inhibitory activities against the parasitic protozoa Trichomonas vaginalis human strain G3 that causes the sexually transmitted disease trichomoniasis in women, Tritrichomonas foetus bovine strain D1 that causes sexually transmitted diseases in farm animals (bulls, cows, and pigs), Tritrichomonas foetus-like strain C1 that causes diarrhea in domestic animals (cats and dogs), and bacteria and fungi. The anthraquinones assessed for their inhibitory activity were anthraquinone, aloe-emodin (1,8-dihydroxy-3-hydroxymethylanthraquinone), anthrarufin (1,5-dihydroxyanthraquinone), chrysazin (1,8-dihydroxyanthraquinone), emodin (1,3,8-trihydroxy-6-methylanthraquinone), purpurin (1,2,4-trihydroxyanthraquinone), and rhein (1,8-dihydroxy-3-carboxyanthraquinone). Their activities were determined in terms of IC50 values, defined as the concentration that inhibits 50% of the cells under the test conditions and calculated from linear dose response plots for the parasitic protozoa, and zone of inhibition for bacteria and fungi, respectively. The results show that the different substituents on the anthraquinone ring seem to influence the relative potency. Analysis of the structure-activity relationships in protozoa indicates that the aloe-emodin and chrysazin with the highest biological activities merit further study for their potential to help treat the diseases in women and domestic and farm animals. Emodin also exhibited antifungal activity against Candida albicans. The suggested mechanism of action and the additional reported beneficial biological properties of anthraquinones suggest that they have the potential to ameliorate a broad spectrum of human diseases.

Diabetes care in remote Australia: the antenatal, postpartum and inter-pregnancy period.

BACKGROUND: Aboriginal and Torres Strait Islander women experience high rates of diabetes in pregnancy (DIP), contributing to health risks for mother and infant, and the intergenerational cycle of diabetes. By enhancing diabetes management during pregnancy, postpartum and the interval between pregnancies, the DIP Partnership aims to improve health outcomes and reduce risks early in the life-course. We describe a mixed methods formative study of health professional's perspectives of antenatal and post-partum diabetes screening and management, including enablers and barriers to care. METHODS: Health professionals involved in providing diabetes care in pregnancy, from a range of health services across the Northern Territory, completed the survey (n = 82) and/or took part in interviews and/or focus groups (n = 62). RESULTS: Qualitative findings highlighted factors influencing the delivery of care as reported by health professionals, including: whose responsibility it is, access to care, the baby is the focus and pre-conception care. The main challenges were related to: disjointed systems and confusion around whose role it is to provide follow-up care beyond six weeks post-partum. Quantitative findings indicated that the majority of health professionals reported confidence in their own skills to manage women in the antenatal period (62%, 40/79) and slightly lower rates of confidence in the postpartum interval (57%, 33/58). CONCLUSION: These findings regarding whose role it is to provide postpartum care, along with opportunities to improve communication pathways and follow up care have informed the design of a complex health intervention to improve health systems and the provision of DIP related care.

Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance.

Fourteen novel arene RuII , and cyclopentadienyl (Cpx ) RhIII and IrIII complexes containing an N,N'-chelated pyridylimino- or quinolylimino ligand functionalized with the antimalarial drug sulfadoxine have been synthesized and characterized, including three by X-ray crystallography. The rhodium and iridium complexes exhibited potent antiplasmodial activity with IC50 values of 0.10-2.0 µm in either all, or one of the three Plasmodium falciparum assays (3D7 chloroquine sensitive, Dd2 chloroquine resistant and NF54 sexual late stage gametocytes) but were only moderately active towards Trichomonas vaginalis. They were active in both the asexual blood stage and the sexual late stage gametocyte assays, whereas the clinical parent drug, sulfadoxine, was inactive. Five complexes were moderately active against Mycobacterium tuberculosis (IC50 <6.3 µm), while sulfadoxine showed no antitubercular activity. An increase in the size of both the Cpx ligand and the aromatic imino substituent increased hydrophobicity, which resulted in an increase in antiplasmodial activity.

Cinnamoyl-Oxaborole Amides: Synthesis and Their in Vitro Biological Activity.

Due to the increased interest in their application in the treatment of infectious diseases, boron-containing compounds have received a significant coverage in the literature. Herein, a small set of novel cinnamoly-oxaborole amides were synthesized and screened against nagana Trypanosoma brucei brucei for antitrypanosomal activity. Compound 5g emerged as a new hit with an in vitro IC50 value of 0.086 µM against T. b. brucei without obvious inhibitory activity against HeLa cell lines. The same series was also screened against other human pathogens, including Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), for which moderate to weak activity (10 to >125 µM) was observed. Similarly, these compounds exhibited moderate activity against the human protozoal pathogen Trichomonas vaginalis with no observed effect on common microbiome bacterial species. The cross-species inhibitory activity presents the possibility of these compounds serving as broad-spectrum antibiotics for these prevalent three human pathogens.

Recent developments in drug discovery against the protozoal parasites Cryptosporidium and Toxoplasma.

Apicomplexan parasites cause some of the most devastating human diseases, including malaria, toxoplasmosis, and cryptosporidiosis. New drug discovery is imperative in light of increased resistance. In this digest article, we briefly explore some of the recent and promising developments in new drug discovery against two apicomplexan parasites, Cryptosporidium and Toxoplasma.

An 18S rRNA Workflow for Characterizing Protists in Sewage, with a Focus on Zoonotic Trichomonads.

Microbial eukaryotes (protists) are important components of terrestrial and aquatic environments, as well as animal and human microbiomes. Their relationships with metazoa range from mutualistic to parasitic and zoonotic (i.e., transmissible between humans and animals). Despite their ecological importance, our knowledge of protists in urban environments lags behind that of bacteria, largely due to a lack of experimentally validated high-throughput protocols that produce accurate estimates of protist diversity while minimizing non-protist DNA representation. We optimized protocols for detecting zoonotic protists in raw sewage samples, with a focus on trichomonad taxa. First, we investigated the utility of two commonly used variable regions of the 18S rRNA marker gene, V4 and V9, by amplifying and Sanger sequencing 23 different eukaryotic species, including 16 protist species such as Cryptosporidium parvum, Giardia intestinalis, Toxoplasma gondii, and species of trichomonad. Next, we optimized wet-lab methods for sample processing and Illumina sequencing of both regions from raw sewage collected from a private apartment building in New York City. Our results show that both regions are effective at identifying several zoonotic protists that may be present in sewage. A combination of small extractions (1 mL volumes) performed on the same day as sample collection, and the incorporation of a vertebrate blocking primer, is ideal to detect protist taxa of interest and combat the effects of metazoan DNA. We expect that the robust, standardized methods presented in our workflow will be applicable to investigations of protists in other environmental samples, and will help facilitate large-scale investigations of protistan diversity.

Phytochemical-rich foods inhibit the growth of pathogenic trichomonads.

BACKGROUND: Plants produce secondary metabolites that often possess widespread bioactivity, and are then known as phytochemicals. We previously determined that several phytochemical-rich food-derived preparations were active against pathogenic foodborne bacteria. Trichomonads produce disease (trichomoniasis) in humans and in certain animals. Trichomonads are increasingly becoming resistant to conventional modes of treatment. It is of interest to test bioactive, natural compounds for efficacy against these pathogens. METHODS: Using a cell assay, black tea, green tea, grape, pomegranate, and jujube extracts, as well as whole dried jujube were tested against three trichomonads: Trichomonas vaginalis strain G3 (found in humans), Tritrichomonas foetus strain D1 (found in cattle), and Tritrichomonas foetus-like organism strain C1 (found in cats). The most effective of the test substances was subsequently tested against two metronidazole-resistant Trichomonas vaginalis strains, and on normal mucosal flora. RESULTS: Black tea extract inhibited all the tested trichomonads, but was most effective against the T. vaginalis organisms. Inhibition by black tea was correlated with the total and individual theaflavin content of the two tea extracts determined by HPLC. Metronidazole-resistant Trichomonas vaginalis strains were also inhibited by the black tea extract. The response of the organisms to the remaining preparations was variable and unique. We observed no effect of the black tea extract on common normal flora bacteria. CONCLUSIONS: The results suggest that the black tea, and to a lesser degree green tea, grape seed, and pomegranate extracts might present possible natural alternative therapeutic agents to treat Trichomonas vaginalis infections in humans and the related trichomonad infections in animals, without negatively affecting the normal flora.

Synthesis and antiprotozoal activity of mono- and bis-uracil isatin conjugates against the human pathogen Trichomonas vaginalis.

A library of mono- and bis-uracil isatin conjugates were synthesized and subjected for the assessment of their in vitro activity against the protozoal pathogen Trichomonas vaginalis. The structure activity studies (SAR) revealed that the bis-uracil-isatin based conjugates were more effective than their corresponding mono conjugates in inhibiting the growth of T. vaginalis at approximately 10 µM with no visual effect on mammalian cells at the same concentration.

Synthesis and preliminary in vitro activity of mono- and bis-1H-1,2,3-triazole-tethered ß-lactam-isatin conjugates against the human protozoal pathogen Trichomonas vaginalis.

In this study, we describe the synthesis of mono- and bis-1H-1,2,3-triazole-tethered ß-lactam-isatin conjugates using copper-catalysed azide-alkyne cycloaddition reaction between mono- and di-propargylated azetidin-2-ones and N-alkylazido isatins. The synthesized conjugates were evaluated for their preliminary in vitro analysis against Trichomonas vaginalis at 50 µM. The efficacy of synthesized hybrids was observed to depend on the substituent at N-1 position of ß-lactam ring, as well as the presence of single/double 1H-1,2,3-triazole linker. Among the synthesized conjugates, the presence of a p-tolyl substituent at N-1 of ß-lactam ring was preferred for good activity profiles while the increase in spacer length did not influence the efficacy of the compounds. Compounds with high levels of potency were further analysed to determine their IC50 values, as well as cytotoxicity profiles against mammalian cells. The most active compound in the synthesized conjugates displayed an IC50 value of 10.49 µM against cultured G3 strain of T. vaginalis and was non-toxic to cultured mammalian HeLa cells at the same concentration.

A cysteine protease inhibitor rescues mice from a lethal Cryptosporidium parvum infection.

Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium parvum, can stunt infant growth and can be lethal in immunocompromised individuals. The most widely used drugs for treating cryptosporidiosis are nitazoxanide and paromomycin, although both exhibit limited efficacy. To investigate an alternative approach to therapy, we demonstrate that the clan CA cysteine protease inhibitor N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K11777) inhibits C. parvum growth in mammalian cell lines in a concentration-dependent manner. Further, using the C57BL/6 gamma interferon receptor knockout (IFN-γR-KO) mouse model, which is highly susceptible to C. parvum, oral or intraperitoneal treatment with K11777 for 10 days rescued mice from otherwise lethal infections. Histologic examination of untreated mice showed intestinal inflammation, villous blunting, and abundant intracellular parasite stages. In contrast, K11777-treated mice (210 mg/kg of body weight/day) showed only minimal inflammation and no epithelial changes. Three putative protease targets (termed cryptopains 1 to 3, or CpaCATL-1, -2, and -3) were identified in the C. parvum genome, but only two are transcribed in infected mammals. A homology model predicted that K11777 would bind to cryptopain 1. Recombinant enzymatically active cryptopain 1 was successfully targeted by K11777 in a competition assay with a labeled active-site-directed probe. K11777 exhibited no toxicity in vitro and in vivo, and surviving animals remained free of parasites 3 weeks after treatment. The discovery that a cysteine protease inhibitor provides potent anticryptosporidial activity in an animal model of infection encourages the investigation and development of this biocide class as a new, and urgently needed, chemotherapy for cryptosporidiosis.

Natural Products as Drug Candidates for Redox-Related Human Disease.

This Special Issue presented recent progress on natural products that serve as drug candidates for redox-related human diseases [...].

S-Adenosylhomocysteine hydrolase of the protozoan parasite Trichomonas vaginalis: potent inhibitory activity of 9-(2-deoxy-2-fluoro-ß,D-arabinofuranosyl)adenine.

In the present study, we carried out a structure-activity analysis in Trichomonas vaginalis of a series of adenosine and uridine analogues. The most potent compounds were found to be 2' and 3' modified adenosine analogues some of which are potent inhibitors of S-adenosylhomocysteine hydrolase. The 9-(2-deoxy-2-fluoro-ß,D-arabinofuranosyl)adenine compound was more potent than metronidazole, a current FDA approved and commonly prescribed drug for treatment of trichomoniasis. Its IC(50) was 0.09 µM compared to 0.72 µM for metronidazole.

Advances in Antifungal Development: Discovery of New Drugs and Drug Repurposing.

This Special Issue of Pharmaceuticals describes recent advances accomplished in the field of antifungal development, especially the discovery of new drugs and drug repurposing [...].

Nipped in the Bud: COVID-19 Reveals the Malleability of STEM Student Self-Efficacy.

When a global pandemic hits during a longitudinal study of biology student success, researchers can unearth rich information about student resilience. By sharing case studies from two demographically different midsized 4-year institutions, this article illustrates the aspects of student self-efficacy beliefs that were undercut by the shift to emergency remote instruction (ERI) in introductory biology courses in Spring 2020: agency and belonging. By assessing student predictions of exam performance and analyzing themes from 276 student narrative surveys, we highlight the power of a careful balance between cognitive and social interventions to help students recover. Students in this study showed a 50% loss of efficacy beliefs after ERI (midsemester) but were able to improve to at least 75% above starting efficacy beliefs after instructor interventions. Thus, we also show how academic efficacy is highly malleable and is mediated in relationships. In turn, we demonstrate a new assessment model that uses student narrative writing to reveal "invisible" threats to students' perceptions of their capacity to succeed. Finally, we generalize from their findings to provide recommendations for effective strategies for supporting those students for whom every semester feels like a pandemic.

Antifungal Efficacy of Redox-Active Natamycin against Some Foodborne Fungi-Comparison with Aspergillus fumigatus.

The fungal antioxidant system is one of the targets of the redox-active polyene antifungal drugs, including amphotericin B (AMB), nystatin (NYS), and natamycin (NAT). Besides medical applications, NAT has been used in industry for preserving foods and crops. In this study, we investigated two parameters (pH and food ingredients) affecting NAT efficacy. In the human pathogen, Aspergillus fumigatus, NAT (2 to 16 µg mL-1) exerted higher activity at pH 5.6 than at pH 3.5 on a defined medium. In contrast, NAT exhibited higher activity at pH 3.5 than at pH 5.6 against foodborne fungal contaminants, Aspergillus flavus, Aspergillus parasiticus, and Penicillium expansum, with P. expansum being the most sensitive. In commercial food matrices (10 organic fruit juices), food ingredients differentially affected NAT antifungal efficacy. Noteworthily, NAT overcame tolerance of the A. fumigatus signaling mutants to the fungicide fludioxonil and exerted antifungal synergism with the secondary metabolite, kojic acid (KA). Altogether, NAT exhibited better antifungal activity at acidic pH against foodborne fungi; however, the ingredients from commercial food matrices presented greater impact on NAT efficacy compared to pH values. Comprehensive determination of parameters affecting NAT efficacy and improved food formulation will promote sustainable food/crop production, food safety, and public health.

Gold(I) Phosphine Derivatives with Improved Selectivity as Topically Active Drug Leads to Overcome 5-Nitroheterocyclic Drug Resistance in Trichomonas vaginalis.

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

Bioactive half-sandwich Rh and Ir bipyridyl complexes containing artemisinin.

Reaction of dihydroartemisinin (DHA) with 4-methyl-4'-carboxy-2,2'-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1-6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC50 values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06-9.23 µM versus 0.24-7.2 µM, respectively). Overall, the iridium complexes (1-3) are more potent compared to the rhodium derivatives (4-6), and complex 3 emerges as the most promising candidate for future studies.

Anti-Parasitic Activity of Cherry Tomato Peel Powders.

Trichomoniasis in humans, caused by the protozoal parasite Trichomonas vaginalis, is the most common non-viral sexually transmitted disease, while Tritrichomonas foetus causes trichomonosis, an infection of the gastrointestinal tract and diarrhea in farm animals and domesticated cats. As part of an effort to determine the inhibitory effects of plant-based extracts and pure compounds, seven commercially available cherry tomato varieties were hand-peeled, freeze-dried, and pounded into powders. The anti-trichomonad inhibitory activities of these peel powders at 0.02% concentration determined using an in vitro cell assay varied widely from 0.0% to 66.7% against T. vaginalis G3 (human); from 0.9% to 66.8% for T. foetus C1 (feline); and from 0.0% to 81.3% for T. foetus D1 (bovine). The organic Solanum lycopersicum var. cerasiforme (D) peels were the most active against all three trichomonads, inhibiting 52.2% (G3), 66.8% (C1), and 81.3% (D1). Additional assays showed that none of the powders inhibited the growth of foodborne pathogenic bacteria, pathogenic fungi, or non-pathogenic lactobacilli. Tomato peel and pomace powders with high content of described biologically active compounds could serve as functional food and feed additives that might help overcome adverse effects of wide-ranging diseases and complement the treatment of parasites with the anti-trichomonad drug metronidazole.