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Background: Evaluating infection in home‐based primary care is challenging, and these challenges may impact antibiotic prescribing. A refined understanding of antibiotic decision‐making in this setting can inform strategies to promote antibiotic stewardship. This study investigated antibiotic decision‐making by exploring the perspectives of clinicians in home‐based primary care. Methods: Clinicians from the Department of Veterans Affairs Home‐Based Primary Care Program were recruited. Semi‐structured interviews were conducted from June 2022 through September 2022 using a discussion guide. Transcripts were analyzed using grounded theory. The constant comparative method was used to develop a coding structure and to identify themes. Results: Theoretical saturation was reached after 22 clinicians (physicians, n = 7; physician assistants, n = 2, advanced practice registered nurses, n = 13) from 19 programs were interviewed. Mean age was 48.5 ± 9.3 years, 91% were female, and 59% had ≥6 years of experience in home‐based primary care. Participants reported uncertainty about the diagnosis of infection due to the characteristics of homebound patients (atypical presentations of disease, presence of multiple chronic conditions, presence of cognitive impairment) and the challenges of delivering medical care in the home (limited access to diagnostic testing, suboptimal quality of microbiological specimens, barriers to establishing remote access to the electronic health record). When faced with diagnostic uncertainty about infection, participants described many factors that influenced the decision to prescribe antibiotics, including those that promoted prescribing (desire to avoid hospitalization, pressure from caregivers, unreliable plans for follow‐up) and those that inhibited prescribing (perceptions of antibiotic‐associated harms, willingness to trial non‐pharmacological interventions first, presence of caregivers who were trusted by clinicians to monitor symptoms). Conclusions: Clinicians face the difficult task of balancing diagnostic uncertainty with many competing considerations during the treatment of infection in home‐based primary care. Recognizing these issues provides insight into strategies to promote antibiotic stewardship in home care settings. [ABSTRACT FROM AUTHOR]

The growing number of people living with dementia (PLWD) requires a coordinated clinical response to deliver pragmatic, evidence‐based interventions in frontline care settings. However, infrastructure to support such a response is lacking. Moreover, there are too few researchers conducting rigorous embedded pragmatic clinical trials (ePCTs) to make the vision of high quality, widely accessible dementia care a reality. National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer's disease and Related Dementias Clinical Trials (IMPACT) Collaboratory seeks to improve the pipeline of early career researchers qualified to lead ePCTs by funding career development awards. Even with support from the Collaboratory, awardees face practical and methodological challenges to success, recently exacerbated by the COVID‐19 pandemic. We first describe the training opportunities and support network for the IMPACT CDA recipients. This report then describes the unique career development challenges faced by early‐career researchers involved in ePCTs for dementia care. Topics addressed include challenges in establishing a laboratory, academic promotion, mentoring and professional development, and work‐life balance. Concrete suggestions to address these challenges are offered for early‐career investigators, their mentors, and their supporting institutions. While some of these challenges are faced by researchers in other fields, this report seeks to provide a roadmap for expanding the work of the IMPACT Collaboratory and initiating future efforts to recruit, train, and retain talented early‐career researchers involved in ePCTs for dementia care. [ABSTRACT FROM AUTHOR]

Leishmania has a remarkable ability to proliferate under widely fluctuating levels of essential nutrients, such as glucose. For this, the parasite is heavily dependent on its gluconeogenic machinery. One perplexing aspect of gluconeogenesis in Leishmania is the lack of the crucial gene for pyruvate carboxylase (PC). PC‐catalyzed conversion of pyruvate to oxaloacetate is a key entry point through which gluconeogenic amino acids are funneled into this pathway. The absence of PC in Leishmania thus raises question about the mechanism of pyruvate entry into the gluconeogenic route. In the present study, we report that this task is accomplished in Leishmania major through a novel functional partnership between its mitochondrial malic enzyme (LmME) and carbonic anhydrase 1 (LmCA1). Using a combination of pharmacological inhibition studies with genetic manipulation, we show that both of these enzymes are necessary for promoting gluconeogenesis and supporting parasite growth under glucose‐limiting conditions. Functional cross‐talk between LmME and LmCA1 was evident when it was observed that the growth retardation caused by inhibition of any one of these enzymes could be protected to a significant extent by overexpressing the other enzyme. We also found that, although LmCA1 exhibited constitutive expression, the LmME protein level was strongly upregulated under low glucose conditions. Notably, both LmME and LmCA1 were found to be important for survival of Leishmania amastigotes within host macrophages. Taken together, our results indicate that LmCA1 by virtue of its CO2 concentrating ability stimulates LmME‐catalyzed pyruvate carboxylation, thereby driving gluconeogenesis through the pyruvate–malate–oxaloacetate bypass pathway. Additionally, our study establishes LmCA1 and LmME as promising therapeutic targets. [ABSTRACT FROM AUTHOR]

This paper presents the development of a new double integral inequality (II) with the motivation of yielding quadratic approximation. It is well known that approximating integral quadratic terms with quadratic terms involves a certain degree of conservatism. In this paper, a sufficient gap has been identified in the approximation of two recent IIs reported in the literature, thereby leading to the new double II. The developed inequality has been applied to access the stability of a linear retarded system to estimate a maximum delay upper‐bound. Furthermore, a mathematical relationship of the new double II with existing inequalities is discussed to show that the developed inequality is more general, effective and bears less computational burden. Four numerical examples are given to validate the authors' claim with regard to the effective estimate of delay bound results for a linear retarded system. [ABSTRACT FROM AUTHOR]

A series of peptides (1‐3) containing m‐nitrocinnamic acid, α‐aminoisobutyric acid (Aib) and L‐leucine has been synthesized and their antileishmanial propensities have been studied. The compound 1 was synthesized by condensation reaction of 3‐nitrobenzaldehyde and malonic acid. The compound 1 forms duplex by intermolecular hydrogen bonding interactions in solid state and finally self‐assemble to form supramolecular helix through C‐H⋅⋅⋅O hydrogen bonds. The peptide 2 shows antiparallel sheet‐like assembly through intermolecular N‐H⋅⋅⋅O and C‐H⋅⋅⋅O hydrogen bonding interactions. The peptide 3 adopts extended conformation and self‐assemble to form bowl‐like morphology. Moreover, the peptide 3 exhibits significant growth inhibition property on Leishmania major promastigotes with an IC50 value of 13 μg/ml. But compound 1 and peptide 2 have IC50 values 100 μg/ml and 41 μg/ml respectively. The higher lipophilicity of peptide 3 may increase the chances of reaching this intracellular parasite. Thus peptide 3 shows selective toxicity towards Leishmania (IC50=13 μg/ml) and compared to several existing standard antileishmanial drugs like pentastam (IC50 > 64 μg/ml), sodium stibogluconate (IC50 > 64 μg/ml) or ketoconazole (IC50=72 μg/ml), peptide 3 shows at least 2–6 times higher potency. Antileishmanial property: Lipophilic peptide containing m‐nitrocinnamic acid, α‐aminoisobutyric acid and L‐leucine shows selective toxicity towards Leishmania major parasite (IC50=13 μg/ml) and compared to several existing standard antileishmanial drugs like pentastam (IC50 > 64 μg/ml), sodium stibogluconate (IC50 > 64 μg/ml) or ketoconazole (IC50=72 μg/ml), shows at least 2–6 times higher potency. Also, the peptide does not have significant harmful effect on macrophage cell line. [ABSTRACT FROM AUTHOR]

Abstract: The dipeptides 1–4 with a triazole containing synthetic amino acid and Leu/ Phe/ Val/ Gly have been designed and synthesized as a potent antileishmanial agent. The 1‐(2‐Amino‐phenyl)‐1H‐[1, 2,3] triazole‐4‐carboxylic acid was synthesized using click chemistry approach. From X‐ray crystallography, the peptide 1 containing a Leu residue at C‐terminus adopts kink like structure but there is no intramolecular hydrogen bond. So, the hydrogen bonding sites are free and allowed for intermolecular interaction with the guests. The phenylalanine analogue 2 where the phenyl and triazole rings are perpendicular to each other also form supramolecular column‐like structure through π‐π stacking interaction. The incorporation of a triazole containing synthetic amino acid at the N‐terminus enhances its anti‐parasites activity. The properties such as lipophilicity and cytotoxicity, are relevant factors for the design of new antileishmanial agent. IC50 value were calculated for dipeptides 1–4 using normal growth inhibition strategy. For dipeptide 1, IC50 value is 11μg/ml and the Phe containing dipeptide 2 exhibits IC50 21.17μg/ml on Leishmania major promastigotes. But the Val and Gly containing dipeptides 3 and 4 have IC50 values 138.23 μg/ml and 21.75 μg/ml respectively. The higher lipophilicity of dipeptide 1 is likely to improve the chances of reaching this intracellular parasite. The experimental result show that the triazole‐based dipeptide 1 is promising as antileishmanial agent. [ABSTRACT FROM AUTHOR]