Implementing virtual primary care: experiences, perspectives and identification of improvement opportunities in an academic primary care setting.

BACKGROUND: One of the biggest changes to primary care triggered by the COVID-19 pandemic was the rapid integration of virtual care (VC). VC offers benefits to patients and providers but implementation presents challenges. METHODS: This study is a secondary analysis of a 2021 quality improvement (QI) driven environmental scan comprising a survey and 1:1 interviews, at the Department of Family and Community Medicine at the University of Toronto. The scan aimed to understand the current and desired future use of VC at the 14 sites. RESULTS: The survey was completed by all sites between July and October 2021 and 1:1 interviews were conducted between October and November 2021 with 12 of the 14 site/QI leads. VC was seen as convenient and flexible, and as enabling continuity of care for patients who could not easily attend in-person. Factors enabling implementation of VC included leadership at both the system and local level; a shared understanding of VC on the part of providers, patients and clinical staff; and technological and administrative readiness. Challenges included the need for triage algorithms; incongruent expectations of VC by patients and providers; technology issues; increased administrative burden; and impacts on medical education. All anticipated that some degree of VC would continue in future. CONCLUSIONS: VC offered benefits but it also impacted clinical routines and administrative processes creating new forms of work for clinicians and staff. Patient education is needed to ensure that their expectations of VC align with those of providers. Research and QI efforts are required to optimise the use of VC in primary care.

Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor.

Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.

Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.

Design, synthesis and antiviral evaluation of 2'-C-methyl branched guanosine pronucleotides: the discovery of IDX184, a potent liver-targeted HCV polymerase inhibitor.

BACKGROUND: Ribonucleoside analogs possessing a ß-methyl substituent at the 2'-position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure-activity relationships of several phosphoramidate diester derivatives of 2'-C-methylguanosine (2'-MeG). CONCLUSION: The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.

Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.

Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.

Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease.

We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.

Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.

Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic ß-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).

Prevention of silica health effects in Italy: current challenges for the Occupational Health and Safety Unit of the Italian National Health Service.

BACKGROUND: Since its foundation in 2002, the Italian Silica Network (NIS), a collaborative network of professionals and public authorities, has been engaged in several aspects of research, control, and prevention of silica exposure and effects, and also in support for compensation claims for silica-related occupational health effects in Italy. METHODS: We start with a report on the NIS point of view concerning the recent scientific results (from epidemiology and laboratory studies), including those carried out by NIS in cooperation with Italian universities and other public agencies. This is followed by a description of the data on silica exposure in different Italian workplaces and guidelines for the management of occupational exposure to silica, as developed by two model regional programmes for the ceramics industry, metal foundries and tunnel excavation. RESULTS: The NIS initiatives highlighted the persistence of workplace conditions posing a significant risk for silica-related health effects, particularly in small industries and workshops. Experimental work has also shown that a number of physical and chemical factors affect the bioreactivity of silica particles. CONCLUSION: Based on NIS experience, it appears clear that currently conditions exist in Italy so as to positively contribute to the WHO Programme for the eradication of silicosis and the other diseases related to silica exposure. In order to achieve this goal, a coordinated and wide-ranging effort is required to reduce the wide gap in specific prevention activities, particularly in small industries and workshops, where high levels of silica exposure sometimes occur.

Synthesis and antiviral evaluation of 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives.

Three 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).

Synthesis and study of 9-deazaguanosine derivatives as potential inhibitors of RNA virus replication.

9-Deazaguanosine and the alpha and beta anomers of its 2'-C-methyl counter part, have been synthesized and evaluated against a broad range of RNA viruses, including hepatitis C virus.

Synthesis and antiviral evaluation of a seven-membered sugar ring nucleoside analog, 9-(5-deoxy-beta-D-allo-septanosyl)-adenine.

The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as the sugar moiety was synthesized and evaluated as a potential inhibitor of several virus replication.

Synthesis and antiviral evaluation of 4-fluoropyrazole-3-carboxamide nucleoside derivatives.

A series of novel 4-fluoro-1H-pyrazole-3-carboxamide nucleoside analogues were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).

2'-C-Methyl branched pyrimidine ribonucleoside analogues: potent inhibitors of RNA virus replication.

RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain 'natural' pyrimidine bases, but possess a beta-methyl substituent at the 2'-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA+), single-stranded negative (ssRNA-) or double-stranded (dsRNA), revealed potent activities for D-2'-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5'-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2'-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.

Synthesis, physicochemical and pharmacokinetic studies of potential prodrugs of beta-L-2'-deoxycytidine, a selective and specific anti-HBV agent.

beta-L-2'-Deoxycytidine (beta-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well N4-derivatization with an N,N-(dimethylamino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, beta-L-dC.

[Survey on health status of workers exposed in the past to carcinogens in a glass factory in Leghorn, Italy]. / Indagine sullo stato di salute di ex-esposti ad agenti cancerogeni di una vetreria industriale.

BACKGROUND: For a few years now in Italy there has been wide discussion on the advisability of developing health surveillance programmes for workers who were exposed to occupational carcinogens in the past (incompliance with Italian D.Lgs. 626/94, art. No. 69). The purpose of the present paper was to contribute to the discussion on operative guidelines for public or private Occupational Health Services intending to address this issue. METHODS: A cross-sectional survey was undertaken on former workers of a glass factory located in Leghorn, Italy. Six hundred and seventy-seven workers discharged in the period 1/1/1942 - 30/6/1992, with at least 1 year of service, resident in the area of Leghorn, were identified from the personnel records of the company and invited to medical examination at the local public Occupational Health Service. A structured questionnaire was developed in order to standardize the collection of occupational and health histories. RESULTS: 370 subjects were examined and for each of them occupational and health histories were collected. Occupational exposure to carcinogens in the factory in the last decades was reconstructed using the workers' occupational histories and the available plant records: 3 periods with different production activities (1942/49, 1950/69, 1970/92), and 4 main carcinogens (asbestos, PAH, silica and glass fibres) were identified. Thirty cancers were recorded and 10 of these were occupationally related. CONCLUSIONS: The health survey allowed occupational exposures to carcinogens to be defined in a factory where historical environmental data were not available. It was also possible to assess individual past occupational risk and provide information to each former worker on his risk, on available preventive measures, and on possible diagnostic, therapeutic and insurance procedures available in relation to diseases related to the different hazards. Via this survey it was also possible to identify and notify the Italian Institute of Insurance against Occupational Diseases and Accidents of 6 cases of bladder cancer, i.e., cancers with long survival that would be impossible to identify via current health data bases.

Novel indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance mutations: synthesis and SAR studies.

The potent anti-HIV-1 activities of L-737,126 (2) and PAS sulfones prompted us to design and test against HIV-1 in acutely infected MT-4 cells a number of novel 1- and 3-benzenesulfonylindoles. Indoles belonging to the 1-benzenesulfonyl series were found poorly or totally inactive. On the contrary, some of the 3-benzenesulfonyl derivatives turned out to be as potent as 2, being endowed with potencies in the low nanomolar concentration range. In particular, (2-methylphenyl)sulfonyl (72) and (3-methylphenyl)sulfonyl (73) derivatives showed EC(50) values of 1 nM. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of 2 furnished derivatives (80 and 83) which showed very potent and selective anti-HIV-1 activity not only against the wt strain, but also against mutants carrying NNRTI-resistant mutations at positions 103 and 181 of the reverse transcriptase gene.

A new class of acyclic nucleoside phosphonates: synthesis and biological activity of 9-[[(phosphonomethyl)aziridin-1-yl]methyl]guanine (PMAMG) and analogues.

A new class of acyclic nucleoside phosphonates PMAMG, PMAMA, PMAMC, and PMAMT (compounds 1, 2, 3 and 4) have been synthesized and tested in vitro against a wide variety of viruses, fungi and bacteria. PMAMG (1) was synthesized by the alkylation reaction of acetylguanine with the phosphonate side-chain, diisopropyl [[2-(bromomethyl)aziridin-1-yl]]methylphosphonate (9), followed by deesterification reaction in the presence of TMSBr. In similar way, PMAMA, PMAMC, and PMAMT were prepared.

Synthesis and studies of 3'-C-trifluoromethyl nucleoside analogues bearing adenine or cytosine as the base.

3'-Deoxy-3'-C-CF3, 2',3'-dideoxy-3'-C-CF3 and 2',3'-unsaturated-3'-C-CF3 nucleoside derivatives of adenosine and cytidine have been synthesized. All these derivatives were prepared by glycosylation of adenine and uracil with a suitable peracylated 3-trifluoromethyl sugar precursor. The resulting protected nucleosides were subject to appropriate chemical modifications to afford the target nucleoside derivatives. Additionally, the chemical stability in acidic and neutral media of the 2',3'-dideoxy-3'-C-CF3 and 2',3'-unsaturated-3'-C-CF3 nucleoside derivatives of adenosine was compared to that of their parent nucleosides 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxy-2',3'-didehydroadenosine (d(4)A). Our results confirm that addition of a trifluoromethyl group at C-3' on such nucleoside derivatives appears to confer increased chemical stability toward acid-catalyzed cleavage of the glycosidic bond comparatively to their parent counterparts. When evaluated for their antiviral activity in cell culture experiments, two compounds, namely, 2',3'-dideoxy-3'-C-CF3-adenosine and 2',3'-dideoxy-2',3'-didehydro-3'-C-CF3-cytidine exhibited moderate anti-HBV activity with EC50 values of 10 and 5 microM, respectively.