Naphthyl bearing 1,3,4-thiadiazoleacetamides targeting the parasitic folate pathway as anti-infectious agents: in silico, synthesis, and biological approach.

Malaria is still a complex and lethal parasitic infectious disease, despite the availability of effective antimalarial drugs. Resistance of malaria parasites to current treatments necessitates new antimalarials targeting P. falciparum proteins. The present study reported the design and synthesis of a series of a 2-(4-substituted piperazin-1-yl)-N-(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl)acetamide hybrids for the inhibition of Plasmodium falciparum dihydrofolate reductase (PfDHFR) using computational biology tools followed by chemical synthesis, structural characterization, and functional analysis. The synthesized compounds were evaluated for their in vitro antimalarial activity against CQ-sensitive PfNF54 and CQ-resistant PfW2 strain. Compounds T5 and T6 are the most active compounds having anti-plasmodial activity against PfNF54 with IC50 values of 0.94 and 3.46 µM respectively. Compound T8 is the most active against the PfW2 strain having an IC50 of 3.91 µM. Further, these active hybrids (T5, T6, and T8) were also evaluated for enzyme inhibition assay against PfDHFR. All the tested compounds were non-toxic against the Hek293 cell line with good selectivity indices. Hemolysis assay also showed non-toxicity of these compounds on normal uninfected human RBCs. In silico molecular docking studies were carried out in the binding pocket of both the wild-type and quadruple mutant Pf-DHFR-TS to gain further insights into probable modes of action of active compounds. ADME prediction and physiochemical properties support their drug-likeness. Additionally, they were screened for antileishmanial activity against L. donovani promastigotes to explore broader applications. Thus, this study provides molecular frameworks for developing potent antimalarials and antileishmanial agents.

Diabetology and Nanotechnology: A Compelling Combination.

The convergence of diabetology and nanotechnology has emerged as a promising synergy with the potential to revolutionize the management and treatment of diabetes mellitus. Diabetes, a complex metabolic disorder affecting millions worldwide, necessitates innovative approaches to enhance monitoring, diagnosis, and therapeutic interventions. Nanotechnology, a burgeoning field that manipulates materials at the nanoscale, offers unprecedented opportunities to address the challenges posed by diabetes. This abstract explores the multifaceted interface between diabetology and nanotechnology, highlighting key areas of integration. Nanotechnology has paved the way for the development of advanced glucose monitoring systems with enhanced accuracy, sensitivity, and patient convenience. Miniaturized biosensors and implantable devices equipped with nanoscale materials enable continuous and real-time glucose monitoring, empowering individuals with diabetes to make timely and informed decisions about their dietary and insulin management. Furthermore, nanotechnology has facilitated breakthroughs in targeted drug delivery, addressing the limitations of conventional therapies in diabetes treatment. Nano-sized drug carriers can improve bioavailability, enable controlled release, and enhance the selectivity of therapeutic agents, minimizing side effects and optimizing treatment outcomes. Moreover, nanoengineered materials have opened avenues for tissue engineering and regenerative medicine, offering the potential to restore damaged pancreatic islets and insulin-producing cells. The amalgamation of diabetology and nanotechnology also holds promise for early disease detection and prevention. Nanoscale diagnostic tools, such as biomarker-based nanoprobes and lab-onchip devices, offer rapid and accurate detection of diabetes-related biomolecules, enabling timely interventions and reducing the risk of complications. However, this compelling combination also presents challenges that warrant careful consideration. Safety, biocompatibility, regulatory approval, and ethical implications are crucial factors that demand meticulous evaluation during the translation of nanotechnology-based solutions into clinical practice. In conclusion, the integration of diabetology and nanotechnology represents a transformative paradigm that has the potential to reshape the landscape of diabetes management. By harnessing the unique properties of nanoscale materials, researchers and clinicians are poised to usher in an era of personalized and precise diagnostics, therapeutics, and preventive strategies for diabetes mellitus. As advancements in nanotechnology continue to unfold, the journey towards realizing the full potential of this compelling combination remains an exciting frontier in medical science.

Identification of new oxospiro chromane quinoline-carboxylate antimalarials that arrest parasite growth at ring stage.

Malaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodium proteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a-o) and carboxylic acids 10(a-b) for the inhibition of Plasmodium N-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. The designed compounds exhibited a glide score of -9.241 to -6.960 kcal/mol for PvNMT and -7.538 kcal/mol for PfNMT model proteins. Development of the synthesized compounds was established via NMR, HRMS and single crystal X-ray diffraction study. The synthesized compounds were evaluated for their in vitro antimalarial efficacy against CQ-sensitive Pf3D7 and CQ-resistant PfINDO lines followed by cell toxicity evaluation. In silico results highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate (9a) as a promising inhibitor with a glide score of -9.084 kcal/mol for PvNMT and -6.975 kcal/mol for PfNMT with IC50 values of 6.58 µM for Pf3D7 line. Furthermore, compounds 9n and 9o exhibited excellent anti-plasmodial activity (Pf3D7 IC50 = 3.96, 6.71 µM, and PfINDO IC50 = 6.38, 2.8 µM, respectively). The conformational stability of 9a with the active site of the target protein was analyzed through MD simulation and was found concordance with in vitro results. Thus, our study provides scaffolds for the development of potent antimalarials targeting both Plasmodium vivax and Plasmodium falciparum.Communicated by Ramaswamy H. Sarma.

Base-free synthesis of benchtop stable Ru(III)-NHC complexes from RuCl3·3H2O and their use as precursors for Ru(II)-NHC complexes.

A series of Ru(III)-NHC complexes, identified as [RuIII(PyNHCR)(Cl)3(H2O)] (1a-c), have been prepared, starting from RuCl3·3H2O following a base-free route. The Lewis acidic Ru(III) centre operates via a halide-assisted, electrophilic C-H activation for carbene generation. The best results were obtained with azolium salts having the I- anion, while ligand precursors with Cl-, BF4-, and PF6- gave no complex formation and those with Br- gave a product with mixed halides. The structurally simple, air and moisture-stable complexes represent rare examples of paramagnetic Ru(III)-NHC complexes. Furthermore, these benchtop stable Ru(III)-NHC complexes were shown to be excellent metal precursors for the synthesis of new [RuII(PyNHCR)(Cl)2(PPh3)2] (2a-c) and [RuII(PyNHCR)(CNCMe)I]PF6 (3a-c) complexes. All the complexes have been characterised using spectroscopic methods, and the structures of 1a, 1b, 2c, and 3a have been determined using the single-crystal X-ray diffraction technique. This work allows easy access to new Ru-NHC complexes for the study of new properties and novel applications.

Effectiveness Of Saddle Block Vs Spinal Anaesthesia In Turp: An Open Label Randomized Control Trial.

BACKGROUND: One of the most frequent diseases among male gender is benign prostatic hyperplasia. Transurethral resection of the prostate (TURP) is a minimally invasive procedure for resection of prostate through endoscopic technique. Recently there was a debate on role of saddle block in TURP. There we aimed to determine the effectiveness of spinal anaesthesia versus saddle block in terms of hemodynamic stability and vasoprbessor requirement in TURP. METHODS: This open label randomized control trial was performed at Hamdard University Hospital, Karachi, Pakistan, during 1st October, 2021 to 31st March, 2022. Male patients of age 45-65 years requiring TURP, with well controlled diabetes and hypertension of ASA grade I-II were included into the study and randomly assigned into two study groups. Patients' parameters including blood pressure, heart rate, mean arterial pressure and oxygen saturation (SPO2) were measured at baseline and intraoperative at every fifth minute interval till surgery completion. Patients' other parameters including age, surgery duration and comorbidity were also recorded. RESULTS: Total 60 patients with 30 patients in each group were enrolled into the study. Maximum fall in systolic blood pressure, diastolic blood pressure, pulse rate and mean arterial pressure from baseline was significantly lower in patients receiving saddle block anaesthesia than spinal anaesthesia. Maximum fall in SPO2 was not significantly different among two study groups. Maximum fall in all parameters excluding SPO2 was significant between two groups for initial 20 minutes of the procedure. No statistically significant maximum fall was seen for all of the parameters beyond 20 minutes of the procedure. Vasopressor consumption was significantly lower in saddle block group than spinal anaesthesia. CONCLUSIONS: Application of saddle block anaesthesia is effective for TURP procedure with controlled hemodynamic status than spinal anaesthesia. Moreover, saddle block requires less vasopressor consumption than spinal anaesthesia technique.

Accelerating Health System Transformation through Research to Achieve the Quadruple Aim and Health Equity.

The Canadian Institutes of Health Research - Institute of Health Services and Policy Research's (IHSPR's) Strategic Plan 2021-2026: Accelerate Health Care System Transformation through Research to Achieve the Quadruple Aim and Health Equity for All (CIHR IHSPR 2021) outlines the Institute's key priority areas for investment and activity over the next five years. IHSPR used an evidence-informed strategic planning process that was pan-Canadian in scope and designed to elicit the health services and policy research priorities of decision makers, providers, researchers, patients, communities and the public. This paper outlines IHSPR's four key strategic priorities for supporting and optimizing research in transforming Canada's healthcare delivery systems over the next five years.

From Strategy to Implementation: Optimizing the Contribution of Health Services and Policy Research to Equitable Healthcare System Transformation.

The Canadian Institutes of Health Research - Institute of Health Services and Policy Research's (IHSPR) Strategic Plan 2021-2026 (CIHR IHSPR 2021) aims to accelerate healthcare system transformation to achieve the Quadruple Aim and health equity through research. This special issue features a collection of commentaries from academic and health system leaders who were invited to respond to IHSPR's strategic plan and share insights regarding the opportunities the plan presents and areas where more attention may be needed. The present paper features a response from the IHSPR team and outlines the next steps regarding implementation. IHSPR is deeply grateful to the commentary authors for their insight, advice and recommendations, which will help to inform the implementation of the plan.

Understanding low-value care and associated de-implementation processes: a qualitative study of Choosing Wisely Interventions across Canadian hospitals.

BACKGROUND: Choosing Wisely (CW) is an international movement comprised of campaigns in more than 20 countries to reduce low-value care (LVC). De-implementation, the reduction or removal of a healthcare practice that offers little to no benefit or causes harm, is an emerging field of research. Little is known about the factors which (i) sustain LVC; and (ii) the magnitude of the problem of LVC. In addition, little is known about the processes of de-implementation, and if and how these processes differ from implementation endeavours. The objective of this study was to explicate the myriad factors which impact the processes and outcomes of de-implementation initiatives that are designed to address national Choosing Wisely campaign recommendations. METHODS: Semi-structured interviews were conducted with individuals implementing Choosing Wisely Canada recommendations in healthcare settings in four provinces. The interview guide was developed using concepts from the literature and the Implementation Process Model (IPM) as a framework. All interviews were conducted virtually, recorded, and transcribed verbatim. Data were analysed using thematic analysis. FINDINGS: Seventeen Choosing Wisely team members were interviewed. Participants identified numerous provider factors, most notably habit, which sustain LVC. Contrary to reporting in recent studies, the majority of LVC in the sample was not 'patient facing'; therefore, patients were not a significant driver for the LVC, nor a barrier to reducing it. Participants detailed aspects of the magnitude of the problems of LVC, providing insight into the complexities and nuances of harm, resources and prevalence. Harm from potential or common infections, reactions, or overtreatment was viewed as the most significant types of harm. Unique factors influencing the processes of de-implementation reported were: influence of Choosing Wisely campaigns, availability of data, lack of targets and hard-coded interventions. CONCLUSIONS: This study explicates factors ranging from those which impact the maintenance of LVC to factors that impact the success of de-implementation interventions intended to reduce them. The findings draw attention to the significance of unintentional factors, highlight the importance of understanding the impact of harm and resources to reduce LVC and illuminate the overstated impact of patients in de-implementation literature. These findings illustrate the complexities of de-implementation.

Using theories and frameworks to understand how to reduce low-value healthcare: a scoping review.

BACKGROUND: There is recognition that the overuse of procedures, testing, and medications constitutes low-value care which strains the healthcare system and, in some circumstances, can cause unnecessary stress and harm for patients. Initiatives across dozens of countries have raised awareness about the harms of low-value care but have had mixed success and the levels of reductions realized have been modest. Similar to the complex drivers of implementation processes, there is a limited understanding of the individual and social behavioral aspects of de-implementation. While researchers have begun to use theory to elucidate the dynamics of de-implementation, the research remains largely atheoretical. The use of theory supports the understanding of how and why interventions succeed or fail and what key factors predict success. The purpose of this scoping review was to identify and characterize the use of theoretical approaches used to understand and/or explain what influences efforts to reduce low-value care. METHODS: We conducted a review of MEDLINE, EMBASE, CINAHL, and Scopus databases from inception to June 2021. Building on previous research, 43 key terms were used to search the literature. The database searches identified 1998 unique articles for which titles and abstracts were screened for inclusion; 232 items were selected for full-text review. RESULTS: Forty-eight studies met the inclusion criteria. Over half of the included articles were published in the last 2 years. The Theoretical Domains Framework (TDF) was the most commonly used determinant framework (n = 22). Of studies that used classic theories, the majority used the Theory of Planned Behavior (n = 6). For implementation theories, Normalization Process Theory and COM-B were used (n = 7). Theories or frameworks were used primarily to identify determinants (n = 37) and inform data analysis (n = 31). Eleven types of low-value care were examined in the included studies, with prescribing practices (e.g., overuse, polypharmacy, and appropriate prescribing) targeted most frequently. CONCLUSIONS: This scoping review provides a rigorous, comprehensive, and extensive synthesis of theoretical approaches used to understand and/or explain what factors influence efforts to reduce low-value care. The results of this review can provide direction and insight for future primary research to support de-implementation and the reduction of low-value care.

Understanding factors critical to the implementation of ehealth in chronic disease management: a realist review protocol.

INTRODUCTION: Canadians are living longer, many with multiple chronic conditions. This population of older, frail Canadians continues to grow in size as do concurrent demands for community-based, outpatient and ambulatory models of care. Ideally, a multifaceted, proactive, planned and integrated care model includes ehealth. Although several factors are known to facilitate the implementation of ehealth in chronic disease management (CDM), for example, adequate support, usability, alignment of programme objectives, there is a growing body of inconclusive evidence on what is critical for implementation. We aim to achieve a fulsome understanding of factors critical to implementation by conducting a realist review-an approach suitable for understanding complex interventions. Our proposed review will identify factors critical to the implementation of ehealth in CDM (heart failure, chronic obstructive pulmonary disease, chronic kidney disease and/or diabetes (type 1 or 2)) without limitations to care setting, language, publication year or geography. Findings will be presented in configurations of contexts, mechanisms and outcomes (CMOs). METHODS AND ANALYSIS: A search strategy will be iteratively developed based on the concepts of 'implementation' and 'adoption' of 'ehealth' interventions used within 'CDM' to identify the peer-reviewed and grey literature published before 31 March 2021 from five databases (Medline, Embase, Cochrane, CINAHL and PsychInfo) on ehealth interventions actively involving a healthcare provider for CDM among adults. Data extraction and synthesis will be guided by Realist and Meta-review Evidence Synthesis: Evolving Standards (RAMESES) guidelines informing core concepts of CMOs, and a study output will include a middle-range-theory describing the implementation of ehealth in CDM. ETHICS AND DISSEMINATION: Findings will be published in an open-access peer-reviewed journal and presented at relevant conferences. A multistakeholder (patients, caregivers, healthcare providers and practitioners, decision-makers and policy-makers) perspective will be used in our dissemination approach. No formal ethics approval is required for this review. PROSPERO REGISTRATION NUMBER: CRD42020208275.

Unmet psycho-social needs, coping strategies and psychological distress among people with cancer: Evidence from Pakistan.

OBJECTIVE: To explore the unmet psychosocial needs, coping styles and psychological distress among people with cancer. METHODS: The cross-sectional correlational study was conducted from May to July 2017 at Shifa International Hospital, Islamabad and Hayatabad Medical Complex, Peshawar, Pakistan which comprised of 182 patients diagnosed with cancer. Data was collected using the Supportive Care Needs Survey-Short Form-34, Mini-Mental Adjustment to Cancer Scale and the Hospital Anxiety Depression Scale. Data was analysed using SPSS 23v. RESULTS: It was found that all psychosocial needs were unmet among all participants (100%) who were suffering from cancer. However, health care information needs and psychological needs emerged to be strikingly unmet with 35.61% and 30.7% respectively. Moreover, maladaptive coping styles were highly endorsed than adaptive coping styles. CONCLUSION: This study pointed towards gaps in delivering quality care services in health care settings, inadequate attention and serious psychological health care neglect of people fighting with life threatening disease, indicating a dire need for proper psychological interventions for effective and holistic treatment planning to improve the whole process of illness and recovery.

Tele-retina screening of diabetic retinopathy among at-risk populations: an economic analysis.

OBJECTIVES: To assess the cost-effectiveness of the pilot Toronto tele-retina screening program in comparison with existing standard of care (SOC) diabetic retinopathy (DR) screening for patients with diabetes mellitus and in a simulated Pan-Ontarian cohort. METHODS: Decision trees were constructed to compare tele-retina to SOC in the pilot and Pan-Ontarian cohort. Cost-effectiveness was assessed as cost per case detected (true-positive) and cost per case correctly diagnosed (true-positive and true-negative results). RESULTS: Pilot program screening costs were $95.77 and $137.56 for tele-retina and SOC, respectively. In the base-case analysis, cost per case correctly detected was $379.06 with tele-retina and $985.56 with SOC, and the cost per case correctly diagnosed was $109.29 and $315.22, respectively. In the sensitivity analysis, cost per case correctly detected was $467.29 with tele-retina and $894.93 with SOC, and the cost per case correctly diagnosed was $136.88 and $250.35, respectively. Pan-Ontarian screening costs were $57.58 and $137.56 for tele-retina and SOC, respectively. The cost per case correctly detected was $281.10 with tele-retina and $982.00 with SOC, and the cost per case correctly diagnosed was $82.21 and $314.14, respectively. For both pilot and Pan-Ontarian sensitivity analyses, tele-retina remained the dominant strategy (ICER <0). CONCLUSIONS: Findings from this study suggest that tele-retina is a more cost-effective means of screening for diabetic retinopathy than the SOC in urban and rural underscreened communities. Subsequent economic studies should focus on evaluations that consider the impact of tele-retina on the prevention of severe vision loss in underscreened urban and rural communities.

Applications of artificial neural networks in health care organizational decision-making: A scoping review.

Health care organizations are leveraging machine-learning techniques, such as artificial neural networks (ANN), to improve delivery of care at a reduced cost. Applications of ANN to diagnosis are well-known; however, ANN are increasingly used to inform health care management decisions. We provide a seminal review of the applications of ANN to health care organizational decision-making. We screened 3,397 articles from six databases with coverage of Health Administration, Computer Science and Business Administration. We extracted study characteristics, aim, methodology and context (including level of analysis) from 80 articles meeting inclusion criteria. Articles were published from 1997-2018 and originated from 24 countries, with a plurality of papers (26 articles) published by authors from the United States. Types of ANN used included ANN (36 articles), feed-forward networks (25 articles), or hybrid models (23 articles); reported accuracy varied from 50% to 100%. The majority of ANN informed decision-making at the micro level (61 articles), between patients and health care providers. Fewer ANN were deployed for intra-organizational (meso- level, 29 articles) and system, policy or inter-organizational (macro- level, 10 articles) decision-making. Our review identifies key characteristics and drivers for market uptake of ANN for health care organizational decision-making to guide further adoption of this technique.

Changes in blood pressure among patients in the Ontario Telehomecare programme: An observational longitudinal cohort study.

Background The objective of this study was to investigate the changes in blood pressure among patients enrolled in the Telehomecare programme in Ontario, Canada. Methods This observational study utilised a prospective longitudinal cohort design, including patients with heart failure and chronic obstructive pulmonary disease enrolled in the Ontario Telehomecare programme from July 2012 to July 2015. The outcome of interest was change in mean (biweekly) systolic and diastolic blood pressure levels over a six-month period. Patient data were extracted from the Ontario Telemedicine Network database, and analysed using generalised linear mixed model procedures. Results Overall, we analysed data for 3513 patients. Patients were on average 74.1 ± 11.4 years of age; almost half were men, 62% had heart failure, 55% chronic obstructive pulmonary disease and 29% diabetes. At baseline, the mean systolic and diastolic blood pressure levels were 130.4 ± 19.1 mmHg and 72.2 ± 12.5 mmHg for the total sample. At six months, the adjusted reduction in systolic and diastolic blood pressure values were 4.0 mmHg (95% confidence interval: -4.5 to -3.5) and 2.7 mmHg (95% confidence interval: -3.1 to -2.4), respectively. In a subgroup of 1220 patients with uncontrolled blood pressure at baseline (systolic/diastolic blood pressure of 150.7 ± 10.2 mmHg/80.2 ± 13.5 mmHg) the adjusted reduction in systolic blood pressure was 12.5 mmHg (95% confidence interval: -13.4 to -11.6) and in diastolic blood pressure was 7.1 mmHg (95% confidence interval: -7.8 to -6.5) over the six-month period. Conclusions Blood pressure levels were significantly reduced in patients enrolled in the Telehomecare programme, with changes being more pronounced in patients with uncontrolled blood pressure. The sustainability of decreased blood pressure on other clinical outcomes needs further evaluation.

A multi-level qualitative analysis of Telehomecare in Ontario: challenges and opportunities.

BACKGROUND: Despite research demonstrating the potential effectiveness of Telehomecare for people with Chronic Obstructive Pulmonary Disease and Heart Failure, broad-scale comprehensive evaluations are lacking. This article discusses the qualitative component of a mixed-method program evaluation of Telehomecare in Ontario, Canada. The objective of the qualitative component was to explore the multi-level factors and processes which facilitate or impede the implementation and adoption of the program across three regions where it was first implemented. METHODS: The study employs a multi-level framework as a conceptual guide to explore the facilitators and barriers to Telehomecare implementation and adoption across five levels: technology, patients, providers, organizations, and structures. In-depth semi-structured interviews and ethnographic observations with program stakeholders, as well as a Telehomecare document review were used to elicit key themes. Study participants (n = 89) included patients and/or informal caregivers (n = 39), health care providers (n = 23), technicians (n = 2), administrators (n = 12), and decision makers (n = 13) across three different Local Health Integration Networks in Ontario. RESULTS: Key facilitators to Telehomecare implementation and adoption at each level of the multi-level framework included: user-friendliness of Telehomecare technology, patient motivation to participate in the program, support for Telehomecare providers, the integration of Telehomecare into broader health service provision, and comprehensive program evaluation. Key barriers included: access-related issues to using the technology, patient language (if not English or French), Telehomecare provider time limitations, gaps in health care provision for patients, and structural barriers to patient participation related to geography and social location. CONCLUSIONS: Though Telehomecare has the potential to positively impact patient lives and strengthen models of health care provision, a number of key challenges remain. As such, further implementation and expansion of Telehomecare must involve continuous assessments of what is working and not working with all stakeholders. Increased dialogue, evaluation, and knowledge translation within and across regions to understand the contextual factors influencing Telehomecare implementation and adoption is required. This can inform decision-making that better reflects and addresses the needs of all program stakeholders.

Synthesis, spectroscopic characterization and comparative DNA binding studies of Schiff base complexes derived from L-leucine and glyoxal.

The mononuclear Schiff base complexes of the type, [ML(CH(3)OH)(2)] [M = Co(II), Ni(II), Cu(II) and Zn(II)] have been synthesized by template condensation of L-leucine and glyoxal. The complexes have been characterized on the basis of the results of the elemental analysis, molar conductance, magnetic susceptibility measurements and spectroscopic studies viz, FT-IR, Mass, (1)H NMR and (13)C NMR spectra. The UV-vis and magnetic moment data revealed an octahedral geometry around Co(II), Ni(II) ion with distortion around Cu(II) ion complex confirmed by EPR data. The conductivity data show a non-electrolytic nature of the complexes. Absorption and fluorescence spectroscopic studies support that all the complexes exhibit a significant binding to calf thymus DNA.