Primary healthcare's carbon footprint and sustainable strategies to mitigate its contribution: a scoping review.

Background: The escalating climate crisis poses a significant threat to global public health. The healthcare sector, designed to protect human health is a major contributor to greenhouse gas emissions, and thus, a key driver of climate degradation. This paradox endangers both planetary and human health, making the decarbonization of healthcare, including primary care, critical.

Publisher Correction: Novel immunotherapeutics against LGR5 to target multiple cancer types.

[Image: see text]

Novel immunotherapeutics against LGR5 to target multiple cancer types.

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5 cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment.

Towards the Targeted Protein Degradation of PRMT1.

Targeting the protein arginine methyltransferase 1 (PRMT1) has emerged as a promising therapeutic strategy in cancer treatment. The phase 1 clinical trial for GSK3368715, the first PRMT1 inhibitor to enter the clinic, was terminated early due to a lack of clinical efficacy, extensive treatment-emergent effects, and dose-limiting toxicities. The incidence of the latter two events may be associated with inhibition-driven pharmacology as a high and sustained concentration of inhibitor is required for therapeutic effect.

Perceptual consequences of online group speech treatment for individuals with Parkinson's disease: A pilot study case series.

Purpose: We examined perceptual changes in the domains of ease of understanding, naturalness, and speech severity, as well as changes in self-perceptions of voice disability, following an online group speech treatment program for people with Parkinson's disease (PD) conducted during the COVID-19 pandemic.

Method: Seven speakers with hypokinetic dysarthria associated with PD participated in a university and community-based online group speech program for 10 weeks. Speech recordings occurred remotely 1 week before and 1 week after the online program.

¿Notas La Diferencia? [Do You Hear the Difference?]: Perceptual Consequences of Intensive Voice Treatment in Spanish Speakers With Parkinson's Disease.

Purpose: The primary objective of this study was to explore the effects of intensive voice-focused treatment on speech parameters in Spanish speakers with dysarthria associated with Parkinson's disease (PD) as perceived by naïve listeners.

Method: Fifteen Spanish speakers with dysarthria associated with PD received the Lee Silverman Voice Treatment (LSVT LOUD) for a month. Voice and speech recordings were conducted pretreatment, posttreatment, and at a 1-month follow-up.

A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase.

Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function.

Ketamine produces no detectable long-term positive or negative effects on cognitive flexibility or reinforcement learning of male rats.

Rationale: Patients with major depressive disorder (MDD) often experience abnormalities in behavioral adaptation following environmental changes (i.e., cognitive flexibility) and tend to undervalue positive outcomes but overvalue negative outcomes.

Disulfide re-bridging reagents for single-payload antibody-drug conjugates.

Numerous antibody-drug conjugate (ADC) linker technologies exist for the synthesis of ADCs with drug-to-antibody ratios (DARs) being an even integer (typically 2, 4 or 8). However, ADCs with odd-integer DARs are significantly harder to synthesise. Here, we report the synthesis of ADCs loaded with a single warhead, using TetraDVP linkers which simultaneously re-bridge all four interchain disulfides of an IgG1 antibody.

Peroxide-cleavable linkers for antibody-drug conjugates.

Antibody-drug conjugates containing peroxide-cleavable arylboronic acid linkers are described, which target the high levels of reactive oxygen species (ROS) in cancer. The arylboronic acid linkers rapidly release a payload in the presence of hydrogen peroxide, but remain stable in plasma. Anti-HER2 and PD-L1 peroxide-cleavable ADCs exhibited potent cytotoxicity .

Acoustic Predictors of Ease of Understanding in Spanish Speakers With Dysarthria Associated With Parkinson's Disease.

Purpose: The purpose of this study was to examine selected baseline acoustic features of hypokinetic dysarthria in Spanish speakers with Parkinson's disease (PD) and identify potential acoustic predictors of ease of understanding in Spanish.

Method: Seventeen Spanish-speaking individuals with mild-to-moderate hypokinetic dysarthria secondary to PD and eight healthy controls were recorded reading a translation of the Rainbow Passage. Acoustic measures of vowel space area, as indicated by the formant centralization ratio (FCR), envelope modulation spectra (EMS), and articulation rate were derived from the speech samples.

Exploring Jordanian emergency registered nurses' experiences of workplace violence: A phenomenological study.

Background: Workplace violence against emergency nurses is an alarming hazard in Jordan, as it is globally. There is no prior research exploring the experiences of workplace violence against Jordanian emergency nurses. This study aimed to investigate Jordanian emergency registered nurses' lived experiences of workplace violence from their patients or relatives while working.

Automatic Assessment of Intelligibility in Noise in Parkinson Disease: Validation Study.

Background: Most individuals with Parkinson disease (PD) experience a degradation in their speech intelligibility. Research on the use of automatic speech recognition (ASR) to assess intelligibility is still sparse, especially when trying to replicate communication challenges in real-life conditions (ie, noisy backgrounds). Developing technologies to automatically measure intelligibility in noise can ultimately assist patients in self-managing their voice changes due to the disease.

All-in-one disulfide bridging enables the generation of antibody conjugates with modular cargo loading.

Antibody-drug conjugates (ADCs) are valuable therapeutic entities which leverage the specificity of antibodies to selectively deliver cytotoxins to antigen-expressing targets such as cancer cells. However, current methods for their construction still suffer from a number of shortcomings. For instance, using a single modification technology to modulate the drug-to-antibody ratio (DAR) in integer increments while maintaining homogeneity and stability remains exceptionally challenging.

Antibody dual-functionalisation enabled through a modular divinylpyrimidine disulfide rebridging strategy.

Herein we report the development of a methodology for the dual-functionalisation of IgG antibodies. This is accomplished through the combination of disulfide rebridging divinylpyrimidine technology, with bicyclononyne and methylcyclopropene handles to facilitate sequential SPAAC and IEDDA reactions. Advantageously, the strategy does not require metal catalysis and avoids the need for purification between functionalisation steps.

Predictors of older adults' chronic pain in the context of opioid adverse drug events.

Background: Factors predictive of chronic pain in older adults could help focus prevention and treatment efforts for those most at risk of chronic pain.

Purpose: The objective of the study was to describe demographic and pain self-management factors predictive of chronic pain in the context of opioid adverse drug events (ADEs) reported for a cohort of older adults within the same year.

Method: The design was a post hoc analysis of 9,095 cases aged 65 years and older from the 2019 National Health Interview Survey that reported chronic pain and 380 cases aged 65 years and older with opioid adverse events reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) during the second quarter of 2019.

Divinylpyrimidine reagents generate antibody-drug conjugates with excellent efficacy and tolerability.

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by and evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.

Rapid and robust cysteine bioconjugation with vinylheteroarenes.

Methods for residue-selective and stable modification of canonical amino acids enable the installation of distinct functionality which can aid in the interrogation of biological processes or the generation of new therapeutic modalities. Herein, we report an extensive investigation of reactivity and stability profiles for a series of vinylheteroarene motifs. Studies on small molecule and protein substrates identified an optimum vinylheteroarene scaffold for selective cysteine modification.

A dual-enzyme cleavable linker for antibody-drug conjugates.

A novel enzyme cleavable linker for antibody-drug conjugates is reported. The 3-O-sulfo-β-galactose linker is cleaved sequentially by two lysosomal enzymes - arylsulfatase A and β-galactosidase - to release the payload in targeted cells. An α-HER2 antibody-drug conjugate synthesised using this highly hydrophilic dual-cleavable linker exhibited excellent cytotoxicity and selectivity.

OXTR rs53576 Variation with Breast and Nipple Pain in Breastfeeding Women.

Thirty percent of women who seek professional breastfeeding support require assistance with ongoing breast and nipple pain and < 50% of women report resolution of their pain. It is unknown if there is a molecular risk for ongoing breast and nipple pain during breastfeeding. Aim -To evaluate associations among breast and nipple pain sensitivity and candidate pain sensitivity single-nucleotide polymorphisms [SNPs], (COMT rs6269, rs4633, rs4818, rs4680 and OXTR rs2254298, rs53576) in breastfeeding women.

Site-selective modification strategies in antibody-drug conjugates.

Antibody-drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies.

Photocatalytic methods for amino acid modification.

Amino acid modification plays an important role across several fields, including synthetic organic chemistry, materials science, targeted drug delivery and the probing of biological function. Although a myriad of methods now exist for the modification of peptides or proteins, many of these target a handful of the most reactive proteinogenic amino acids. Photocatalysis has recently emerged as a mild approach for amino acid modification, generating a sizable toolbox of reactions capable of modifying almost all of the canonical amino acids.

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics.

Hemiasterlin is an antimitotic marine natural product with reported sub-nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four-component Ugi reaction (Ugi-4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI-286), a similarly potent synthetic analogue.

Efficient and selective antibody modification with functionalised divinyltriazines.

A highly efficient disulfide rebridging strategy for the modification of monoclonal antibodies with substituted divinyltriazine linkers is reported. The reaction proceeds efficiently under mild conditions with near stoichiometric quantities of linker. This method of conjugation yields serum stable antibody conjugates with a controlled payload loading of 4.

General dual functionalisation of biomacromolecules via a cysteine bridging strategy.

Site-selective modification of peptides and proteins has resulted in the development of a host of novel tools for the study of cellular systems or the synthesis of enhanced biotherapeutics. There is a need for useful methodologies that enable site-selective modification of native peptides or proteins, which is even more prevalent when modification of the biomolecule with multiple payloads is desired. Herein, we report the development of a novel dual functional divinylpyrimidine (dfDVP) platform that enables robust and modular modification of peptides, antibody fragments and antibodies.