Development and first-stage validation of a digital version of the Digit Symbol Substitution test for use in assessing cognitive function in older people with diabetes.

AIMS: To describe the development and report the first-stage validation of a digital version of the digit symbol substitution test (DSST), for assessment of cognitive function in older people with diabetes. MATERIALS AND METHODS: A multidisciplinary team of experts was convened to conceptualize and build a digital version of the DSST and develop a machine-learning (ML) algorithm to analyse the inputs. One hundred individuals with type 2 diabetes (aged ≥ 60 years) were invited to participate in a one-time meeting in which both the digital and the pencil-and-paper (P&P) versions of the DSST were administered. Information pertaining to demographics, laboratory measurements, and diabetes indices was collected. The correlation between the digital and P&P versions of the test was determined. Additionally, as part of the validation process, the performance of the digital version in people with and without known risk factors for cognitive impairment was analysed. RESULTS: The ML model yielded an overall accuracy of 89.1%. A strong correlation was found between the P&P and digital versions (r = 0.76, p < 0.001) of the DSST, as well as between the ML model and the manual reading of the digital DSST (r = 0.99, p < 0.001). CONCLUSIONS: This study describes the development of and provides first-stage validation data for a newly developed digital cognitive assessment tool that may be used for screening and surveillance of cognitive function in older people with diabetes. More studies are needed to further validate this tool, especially when self-administered and in different clinical settings.

Drug Therapies for Diabetes.

The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.

Probing the molecular interaction of chymotrypsin with organophosphorus compounds by 31P diffusion NMR in aqueous solutions.

In the present study, we applied for the first time (31)P diffusion NMR to resolve different species obtained by the addition of organophosphorus compounds (OP) such as diisopropyl phosphorofluoridate (DFP) or 1-pyrenebutyl phosphorodichloridate (PBPDC) to alpha-chymotrypsin (Cht). (31)P diffusion NMR was used since the products of these reactions constitute a mixture of OP-covalent conjugates of the enzyme and OP-containing hydrolysis products that have noninformative (1)H NMR spectra. It was shown that the peak, attributed to the covalent native diisopropylphosphoryl-Cht (DIP-Cht) conjugate by chemical shift considerations, has a greater diffusion coefficient (D = (0.65 +/- 0.01) x 10(-5) cm(2) s(-1)) than expected from its molecular mass (approximately 25 kDa). This peak was therefore suggested to consist of at least two superimposed signals of diisopropyl phosphoryl (DIP) pools of high and low molecular weights that happen to have the same chemical shift. This conclusion was substantiated by the use of DMSO-d(6) that separated the overlapping signals. Diffusion measurements performed on the extensively dialyzed and unfolded DIP-Cht conjugate still resulted in a high diffusion coefficient ((0.30 +/- 0.05) x 10(-5) cm(2) s(-1)) relative to the assumed molecular mass. This observation was attributed to a dynamic dealkylation at the OP moiety (i.e., aging) that occurred during the relatively long diffusion measurements, where DIP-Cht was converted to the corresponding monoisopropyl phosphoryl Cht (MIP-Cht) conjugate. Homogeneous aged forms of OP-Cht were obtained by use of DFP and heat-induced dealkylation of DIP-Cht, and by PBPDC that provided the aged form via the hydrolysis of a P-Cl bond (PBP-Cht). The thermally stable aged conjugates enabled a reliable determination of the diffusion coefficients over several days of data acquisition, and the values found were (0.052 +/- 0.002) x 10(-5) cm(2) s(-1) and (0.054 +/-0.004) x 10(-5) cm(2) s(-1) for the MIP-Cht and the PBP-Cht adducts, respectively, values in the range expected for a species with a molecular weight of 25 kDa. The advantages and limitations of (31)P diffusion NMR in corroborating the type of species that prevail in such systems are briefly discussed.

The effect of fluoride on the scavenging of organophosphates by human butyrylcholinesterase in buffer solutions and human plasma.

Fluoride ion is a reversible inhibitor of human butyrylcholinesterase (HuBChE) that is a viable drug candidate against organophosphates (OPs) toxicity. Since large numbers of communities in many countries are occasionally exposed to relatively high amount of fluoride, its effect on the kinetics of inhibition of HuBChE by OPs was investigated. In saline phosphate, pH 7.4, fluoride in the lower millimolar range significantly slowed the inhibition of HuBChE by paraoxon, DFP, echothiophate, soman, sarin, and VX. The kinetics of the inhibition was found consistent with the formation of a reversible fluoride-HuBChE complex that is at least 25-fold less active towards phosphorylation or phosphonylation than the free enzyme. Heat inactivation experiments indicate that the binding of fluoride to HuBChE probably involves enhanced cross-domain interaction via hydrogen bonds formation that may decrease enzyme activity. In spite of distinct structural differences among the OP used, the dissociation constants of the fluoride-HuBChE reversible complex varied over a narrow range (KF, 0.31-0.70 mM); however, KF in human plasma increased to 2.75-3.40 mM. 19F-NMR spectroscopy revealed that fluoride ion is complexed to plasma components, an observation that explains in part the apparent increase in KF. Results suggest that an estimate of the relative decrease in the rate of OPs sequestration in presence of fluoride can be obtained from the fraction of the free HuBChE (1 + [F]/K(F))(-1). Considering KF values in human plasma, it is concluded that the scavenging efficacy of OPs by HuBChE is not compromised by the normal concentration range of circulating fluoride ions.