From alcohol detoxification to treatment: A qualitative interview study on perceived barriers and assessed potential of mHealth among individuals postdetoxification.

OBJECTIVE: Most individuals attending detoxification clinics do not pursue subsequent treatment. Earlier research has suggested that emerging technologies like mHealth interventions could address the postdetoxification treatment gap, yet it remains unclear whether patients themselves endorse such approaches. Our study aimed to qualitatively explore perceived treatment barriers and assessed potential of mHealth among individuals who have undergone alcohol detoxification. METHOD: We conducted a single-interview-per-participant qualitative study, sampling participants (n = 23) that had visited the Stockholm substance use disorder emergency department for alcohol-related reasons, of whom n = 8 were purposively included due to having missed their scheduled follow-up outpatient appointment. Semistructured telephone interviews were conducted (2021-2022) and then systematically analyzed using reflexive thematic analysis. RESULTS: Across both areas of analysis, we identified six themes in total. We clustered barriers to postdetoxification treatment into three themes (10 subthemes) that may offer a nuancing perspective on previous research: "Misalignment between the treatment system and the individual," "Practical hurdles" and "Between reaching out and retreating." We identified three themes in participants' perspectives on mHealth as aftercare support, revealing expectations that such an approach may promote "self-awareness on own terms," assist in "navigating from solitary substance use struggles to supportive connections," and "offer a lifeline when needed most," thereby potentially resolving several barriers to treatment. CONCLUSIONS: This first qualitative study on barriers to alcohol treatment and mHealth potential postdetoxification offered various insights that may be translated into effective, real-world solutions to bridge the postdetoxification treatment gap. A natural next step for future research is to evaluate the impact of mHealth postdetoxification. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Late-stage meta-C-H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step.

Catalysed C-H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)-H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C-H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes.

HSQC Spectra Simulation and Matching for Molecular Identification.

In the pursuit of improved compound identification and database search tasks, this study explores heteronuclear single quantum coherence (HSQC) spectra simulation and matching methodologies. HSQC spectra serve as unique molecular fingerprints, enabling a valuable balance of data collection time and information richness. We conducted a comprehensive evaluation of the following four HSQC simulation techniques: ACD/Labs (ACD), MestReNova (MNova), Gaussian NMR calculations (DFT), and a graph-based neural network (ML). For the latter two techniques, we developed a reconstruction logic to combine proton and carbon 1D spectra into HSQC spectra. The methodology involved the implementation of three peak-matching strategies (minimum-sum, Euclidean-distance, and Hungarian distance) combined with three padding strategies (zero-padding, peak-truncated, and nearest-neighbor double assignment). We found that coupling these strategies with a robust simulation technique facilitates the accurate identification of correct molecules from similar analogues (regio- and stereoisomers) and allows for fast and accurate large database searches. Furthermore, we demonstrated the efficacy of the best-performing methodology by rectifying the structures of a set of previously misidentified molecules. This research indicates that effective HSQC spectral simulation and matching methodologies significantly facilitate molecular structure elucidation. Furthermore, we offer a Google Colab notebook for researchers to use our methods on their own data (https://github.com/AstraZeneca/hsqc_structure_elucidation.git).

Investigating the added effects of guidance in digital psychological self-care for alcohol problems (ALVA)-protocol for a randomized factorial optimization trial.

BACKGROUND: The continual development and implementation of effective digital interventions is one important strategy that may serve to bridge the well-known treatment gap related to problematic alcohol use. Research suggests that clinician guidance, provided in different ways during the digital intervention (i.e., written weekly messages, phone calls etc.), can boost intervention engagement and effects. Digital psychological self-care (DPSC) is a new delivery format wherein an unguided digital intervention is provided within the framework of a structured care process that includes initial clinical assessment and follow-up interviews. In a recent feasibility study, a DPSC intervention for problematic alcohol use, ALVA, provided without any extra guidance, was found safe and credible and to have promising within-group effects on alcohol consumption. The aim of the current study is to gather information on the effects and efficiency of different forms of guidance added to ALVA, in order to optimize the intervention. METHODS: This protocol describes a randomized factorial trial where the effects of two different ways of providing guidance (mid-treatment interview, weekly written messages, respectively) in DPSC for problematic alcohol use are investigated. Optimization criteria will be applied to the results regarding how effective the intervention is at reducing alcohol consumption measured by the number of standard drinks per week together with the clinician time spent on guidance. DISCUSSION: This study will investigate the added benefit of different forms of guidance to DPSC for problematic alcohol use. These added effects will be compared to the added cost of guidance, according to pre-defined optimization criteria. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05649982. Registered on 06 December 2022. Prospectively registered.

Regiodivergent Radical Termination for Intermolecular Biocatalytic C-C Bond Formation.

Radical hydrofunctionalizations of electronically unbiased dienes are challenging to render regioselective, because the products are nearly identical in energy. Here, we report two engineered FMN-dependent "ene"-reductases (EREDs) that catalyze regiodivergent hydroalkylations of cyclic and linear dienes. While previous studies focused exclusively on the stereoselectivity of alkene hydroalkylation, this work highlights that EREDs can control the regioselectivity of hydrogen atom transfer, providing a method for selectively preparing constitutional isomers that would be challenging to prepare using traditional synthetic methods. Engineering the ERED from Gluconabacter sp. (GluER) furnished a variant that favors the γ,δ-unsaturated ketone, while an engineered variant from a commercial ERED panel favors the δ,ε-unsaturated ketone. The effect of beneficial mutations has been investigated using substrate docking studies and the mechanism probed by isotope labeling experiments. A variety of α-bromo ketones can be coupled with cyclic and linear dienes. These interesting building blocks can also be further modified to generate difficult-to-access heterocyclic compounds.

Digital interventions targeting excessive substance use and substance use disorders: a comprehensive and systematic scoping review and bibliometric analysis.

Addictive substances are prevalent world-wide, and their use presents a substantial and persistent public health problem. A wide range of digital interventions to decrease use and negative consequences thereof have been explored, differing in approach, theoretical grounding, use of specific technologies, and more. The current study was designed to comprehensively map the recent (2015-2022) extant literature in a systematic manner, and to identify neglected and emerging knowledge gaps. Four major databases (Medline, Web of Science Core Collection, and PsychInfo) were searched using database-specific search strategies, combining terms related to clinical presentation (alcohol, tobacco or other drug use), technology and aim. After deduplication, the remaining n=13,917 unique studies published were manually screened in two stages, leaving a final n=3,056 studies, the abstracts of which were subjected to a tailored coding scheme. Findings revealed an accelerating rate of publications in this field, with randomized trials being the most common study type. Several meta-analyses on the topic have now been published, revealing promising and robust effects. Digital interventions are being offered on numerous levels, from targeted prevention to specialized clinics. Detailed coding was at times made difficult by inconsistent use of specific terms, which has important implications for future meta-analyses. Moreover, we identify several gaps in the extant literature - few health economic assessments, unclear descriptions of interventions, weak meta-analytic support for some type of interventions, and limited research on many target groups, settings and new interventions like video calls, chatbots and artificial intelligence - that we argue are important to address in future research.

Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes.

In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters with aldehyde sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)-C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic ß-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.

Impact of feed, light and access to manipulable material on tail biting in pigs with intact tails.

BACKGROUND: Tail biting (TB) is a welfare issue with economic consequences due to infections and ill-thrift. This study aimed to reduce tail injuries in a high-performing non-tail-docking pig herd. RESULTS: During eleven years preceding the trial, the annual incidence of tail injuries registered at slaughter in pigs from the herd increased from 3% (equivalent to the national mean) to 10%. It was positively correlated to a high weight gain and negatively correlated to daylight length. The overall incidence of tail injuries during the four years preceding the trial was 9.2% with significant differences between four identically structured buildings for fatteners (I < II < III < IV). The feed was enriched with amino acids, minerals and fibres. The buildings used different illumination strategies, I: standard fluorescent tubes with an invisible flickering light of 30-40% for 14 h daily, II: non-flickering led light for 14 h daily, III (control) and IV: standard fluorescent tubes for 2 h daily. IV had free access to manipulable material (hay-silage), while I-III was offered 100-200 g daily. During the adaptation period (6 months), the incidence of tail injuries decreased significantly in all buildings to a mean of 5.4%. The largest decrease (from 11.4 to 4.3%) was obtained in IV. During the trial period (12 months), the mean incidence of tail injuries decreased in all groups to a mean of 3.0%. There were no differences in treatment incidences of individual pigs due to TB between groups, but the use of enriched pellets due to TB in pens was lowest in II. The low incidence of tail injuries was retained during the post-trial period (6 months) when all buildings used artificial illumination for two hours per day. CONCLUSIONS: The incidence of TB in fast growing non-tail-docked pigs in the herd was successfully reduced by supplementing the feed with amino acids, minerals, vitamins and fibres. Additional manipulable material accelerated that process and non-flickering illumination may have had an impact in preventing TB. The results obtained do not support the need for tail-docking of pigs, provided that the needs of the pigs in terms of feed ingredients, stocking density and access to manipulable materials are fulfilled.

Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation.

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules emerging as a powerful modality in drug discovery, with the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these derivatives are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to access fully elaborated heterobifunctional compounds. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C-H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of both CRBN and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.

Selective C-H Iodination of Weinreb Amides and Benzamides through Iridium Catalysis in Solution and under Mechanochemical Conditions.

The acid mediated ortho-iodination of Weinreb amides using a readily available catalyst is described. The selective ortho-iodination of Weinreb amides, challenging substrates in directed C-H activations, and also of benzamides is achieved. The process works under mild conditions and tolerates air and moisture, having a great potential for industrial applications. The methodology can be applied under mechanochemical conditions maintaining the reaction outcome and selectivity.

Heterogeneous Copper-Catalyzed Cross-Coupling for Sustainable Synthesis of Chiral Allenes: Application to the Synthesis of Allenic Natural Products.

Classical Crabbé type SN 2' substitutions of propargylic substrates has served as one of the standard methods for the synthesis of allenes. However, the stereospecific version of this transformation often requires either stoichiometric amounts of organocopper reagents or special functional groups on the substrates, and the chirality transfer efficiency is also capricious. Herein, we report a sustainable methodology for the synthesis of diverse 1,3-di and tri-substituted allenes by using a simple and cheap cellulose supported heterogeneous nanocopper catalyst (MCC-Amp-Cu(I/II)). This approach represents the first example of heterogeneous catalysis for the synthesis of chiral allenes. High yields and excellent enantiospecificity (up to 97 % yield, 99 % ee) were achieved for a wide range of di- and tri-substituted allenes bearing various functional groups. It is worth noting that the applied heterogeneous catalyst could be recycled at least 5 times without any reduced reactivity. To demonstrate the synthetic utility of the developed protocol, we have applied it to the total synthesis of several chiral allenic natural products.

A psychometric evaluation of the Swedish translation of the Perceived Stress Scale: a Rasch analysis.

BACKGROUND: Stress reflects physical and psychological reactions to imposing demands and is often measured using self-reports. A widely-used instrument is the Perceived Stress Scale (PSS), intended to capture more general aspects of stress. A Swedish translation of the PSS is available but has not previously been examined using modern test theory approaches. The aim of the current study is to apply Rasch analysis to further the understanding of the PSS' measurement properties, and, in turn, improve its utility in different settings. METHODS: Data from 793 university students was used to investigate the dimensionality of different version of the PSS (14, 10, and 4 items) as well as potential response patterns among the participants. RESULTS: The current study demonstrates that the PSS-14 has two separate factors, divided between negatively worded items (perceived stress) and positively worded items (perceived [lack of] control), although with only the negative subscale exhibiting good reliability. Response patterns were analyzed using Differential Item Functioning, which did not find an influence of gender on any of the items, but for age regarding the positive subscale (items 6 and 9). The PSS-10 also demonstrated adequate reliability for the negative subscale, but the PSS-4 was not deemed suitable as a unidimensional scale. CONCLUSIONS: Based on the results, none of the versions of the PSS should be used by sum-scoring all of the items. Only the negative items from the PSS-14 or PSS-10 can be used as unidimensional scales to measure general aspects of stress. As for different response patterns, gender may nevertheless be important to consider, as prior research has found differences on several items. Meanwhile, content validity is discussed, questioning the relevance of anger and being upset when measuring more general aspects of stress. Finally, a table to convert the PSS-7 (i.e., negative items) ordinal sum scores to interval level scores is provided.

Ruthenium-Catalyzed Aminocarbonylation with Isocyanates Through Weak Coordinating Groups.

Introducing amide functional groups under mild conditions has growing importance owing to the prevalence of such moiety in biologically active molecules. Herein, we disclose a mild protocol for the directed ruthenium-catalyzed C-H aminocarbonylation with isocyanates as the amidating agents developed through high-throughput experimentation (HTE). The redox-neutral and base-free reaction is guided by weakly Lewis basic functional groups, including anilides, lactams and carbamates to access anthranilamide derivatives. The synthetic utility of this transformation is reflected by large-scale synthesis and late-stage functionalization.

Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification.

Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C-H activations, these arene functionalizations generally require directing groups to enable the C-H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C-H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C-H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C-H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C-H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.

Hybrid Machine Learning Approach to Predict the Site Selectivity of Iridium-Catalyzed Arene Borylation.

The borylation of aryl and heteroaryl C-H bonds is valuable for the site-selective functionalization of C-H bonds in complex molecules. Iridium catalysts ligated by bipyridine ligands catalyze the borylation of the C-H bond that is most acidic and least sterically hindered in an arene, but predicting the site of borylation in molecules containing multiple arenes is difficult. To address this challenge, we report a hybrid computational model that predicts the Site of Borylation (SoBo) in complex molecules. The SoBo model combines density functional theory, semiempirical quantum mechanics, cheminformatics, linear regression, and machine learning to predict site selectivity and to extrapolate these predictions to new chemical space. Experimental validation of SoBo showed that the model predicts the major site of borylation of pharmaceutical intermediates with higher accuracy than prior machine-learning models or human experts, demonstrating that SoBo will be useful to guide experiments for the borylation of specific C(sp2)-H bonds during pharmaceutical development.

Potential drivers of human tick-borne encephalitis in the Örebro region of Sweden, 2010-2021.

Incidence of tick-borne encephalitis (TBE) has increased during the last years in Scandinavia, but the underlying mechanism is not understood. TBE human case data reported between 2010 and 2021 were aggregated into postal codes within Örebro County, south-central Sweden, along with tick abundance and environmental data to analyse spatial patterns and identify drivers of TBE. We identified a substantial and continuing increase of TBE incidence in Örebro County during the study period. Spatial cluster analyses showed significant hotspots (higher number of cases than expected) in the southern and northern parts of Örebro County, whereas a cold spot (lower number of cases than expected) was found in the central part comprising Örebro municipality. Generalised linear models showed that the risk of acquiring TBE increased by 12.5% and 72.3% for every percent increase in relative humidity and proportion of wetland forest, respectively, whereas the risk decreased by 52.8% for every degree Celsius increase in annual temperature range. However, models had relatively low goodness of fit (R2 < 0.27). Results suggest that TBE in Örebro County is spatially clustered, however variables used in this study, i.e., climatic variables, forest cover, water, tick abundance, sheep as indicator species, alone do not explain this pattern.

Digital psychological self-care for problematic alcohol use: feasibility of a new clinical concept.

BACKGROUND: Digital interventions based on cognitive-behavioural therapy and relapse prevention can increase treatment access for people with problematic alcohol use, but for these interventions to be cost-effective, clinician workload needs to remain low while ensuring patient adherence and effects. Digital psychological self-care is the provision of a self-guided digital intervention within a structured care process. AIMS: To investigate the feasibility and preliminary effects of digital psychological self-care for reducing alcohol consumption. METHOD: Thirty-six adults with problematic alcohol use received digital psychological self-care during 8 weeks, including telephone assessments as well as filling out self-rated questionnaires, before, directly after and 3 months after the intervention. Intervention adherence, usefulness, credibility and use of clinician time were assessed, along with preliminary effects on alcohol consumption. The study was prospectively registered as a clinical trial (NCT05037630). RESULTS: Most participants used the intervention daily or several times a week. The digital intervention was regarded as credible and useful, and there were no reported adverse effects. Around 1 h of clinician time per participant was spent on telephone assessments. At the 3-month follow-up, preliminary within-group effects on alcohol consumption were moderate (standardised drinks per week, Hedge's g = 0.70, 95% CI = 0.19-1.21; heavy drinking days, Hedge's g = 0.60, 95% CI = 0.09-1.11), reflecting a decrease from 23 to 13 drinks per week on average. CONCLUSIONS: Digital psychological self-care for reducing alcohol consumption appears both feasible and preliminarily effective and should be further optimised and studied in larger trials.

Comparison of SARS-CoV-2 whole genome sequencing using tiled amplicon enrichment and bait hybridization.

The severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) pandemic has led to extensive virological monitoring by whole genome sequencing (WGS). Investigating the advantages and limitations of different protocols is key when conducting population-level WGS. SARS-CoV-2 positive samples with Ct values of 14-30 were run using three different protocols: the Twist Bioscience SARS­CoV­2 protocol with bait hybridization enrichment sequenced with Illumina, and two tiled amplicon enrichment protocols, ARTIC V3 and Midnight, sequenced with Illumina and Oxford Nanopore Technologies, respectively. Twist resulted in better coverage uniformity and coverage of the entire genome, but has several drawbacks: high human contamination, laborious workflow, high cost, and variation between batches. The ARTIC and Midnight protocol produced an even coverage across samples, and almost all reads were mapped to the SARS-CoV-2 reference. ARTIC and Midnight represent robust, cost-effective, and highly scalable methods that are appropriate in a clinical environment. Lineage designations were uniform across methods, representing the dominant lineages in Sweden during the period of collection. This study provides insights into methodological differences in SARS­CoV­2 sequencing and guidance in selecting suitable methods for various purposes.

Real-time single-molecule 3D tracking in E. coli based on cross-entropy minimization.

Reaching sub-millisecond 3D tracking of individual molecules in living cells would enable direct measurements of diffusion-limited macromolecular interactions under physiological conditions. Here, we present a 3D tracking principle that approaches the relevant regime. The method is based on the true excitation point spread function and cross-entropy minimization for position localization of moving fluorescent reporters. Tests on beads moving on a stage reaches 67 nm lateral and 109 nm axial precision with a time resolution of 0.84 ms at a photon count rate of 60 kHz; the measurements agree with the theoretical and simulated predictions. Our implementation also features a method for microsecond 3D PSF positioning and an estimator for diffusion analysis of tracking data. Finally, we successfully apply these methods to track the Trigger Factor protein in living bacterial cells. Overall, our results show that while it is possible to reach sub-millisecond live-cell single-molecule tracking, it is still hard to resolve state transitions based on diffusivity at this time scale.