Competitive Valerate Binding Enables RuO2-Mediated Butene Electrosynthesis in Water.

The (non)-Kolbe oxidation of valeric acid, sourced from a hydrolysis product of cellulose, provides a sustainable synthetic route to access value-added products, such as butene. An essential mechanistic step preceding product formation involves the oxidative and decarboxylative cleavage of a C-C bond. Yet, the role of the electrode surface in mediating this oxidative step remains an open question: the electron transfer can occur either via an inner-sphere or outer-sphere mechanism. Here, we report the electrochemical, in situ spectroscopic, computational, and reactivity studies of RuO2-mediated oxidative decarboxylation of valeric acid to butene in aqueous electrolytes. We find that carboxylates bind to RuO2 anode surfaces at potential values where decarboxylation products are observed. Our results are consistent with a reaction scheme where the competitive and catalytic oxygen evolution reaction (OER) is impeded by these bound carboxylate species while these species are inert toward butene formation. Our results implicate an outer-sphere electron transfer mechanism for decarboxylation where the surface chemistry of the RuO2 electrode serves to enable higher non-Kolbe reaction selectivity by suppressing the parasitic OER. Our findings delineate interfacial design principles for selective electrochemical systems that utilize water as the ultimate oxidant for sustainable decarboxylation.

Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Real-World Evaluation of the Feasibility, Acceptability and Safety of a Remote, Self-Management Parkinson's Disease Care Pathway: A Healthcare Improvement Initiative.

BACKGROUND: There is significant unmet need for effective and efficiently delivered care for people with Parkinson's disease (PwP). We undertook a service improvement initiative to co-develop and implement a new care pathway, Home Based Care (HBC), based on supported self-management, remote monitoring and the ability to trigger a healthcare contact when needed. OBJECTIVE: To evaluate feasibility, acceptability and safety of Home Based Care. METHODS: We evaluated data from the first 100 patients on HBC for 6 months. Patient monitoring, performed at baseline and 6-monthly, comprised motor (MDS-UPDRS II and accelerometer), non-motor (NMSQ, PDSS-2, HADS) and quality of life (PDQ) measures. Care quality was audited against Parkinson's UK national audit standards. Process measures captured feasibility. Acceptability was assessed using a mixed-methods approach comprising questionnaires and semi-structured interviews. RESULTS: Between October 2019 and January 2021, 108 PwP were enrolled onto HBC, with data from 100 being available at 6 months. Over 90% of all questionnaires were returned, 97% were complete or had < 3 missing items. Reporting and communications occurred within agreed timeframes. Compared with baseline, after 6m on HBC, PD symptoms were stable; more PwP felt listened to (90% vs. 79%) and able to seek help (79% vs. 68%). HBC met 93% of national audit criteria. Key themes from the interviews included autonomy and empowerment. CONCLUSIONS: We have demonstrated acceptability, feasibility and safety of our novel remotely delivered Parkinson's care pathway. Ensuring scalability will widen its reach and realize its benefits for underserved communities, enabling formal comparisons with standard care and cost-effectiveness evaluation.

DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands.

Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.

Telehealth Delivery of Evidence-Based Intervention Within Older Adult Populations: A Scoping Review.

Telehealth services enable individuals to participate in meaningful occupations; however, the evidence on this topic has not been synthesized in older adult populations. This scoping review synthesized the evidence on interventions delivered through telehealth (and the mode of delivery) in occupational therapy for older adult populations. A search for studies on occupational therapy, older adults, and telehealth was performed in six research databases, and identified 536 articles. Four reviewers independently screened the titles and abstracts; and reviewed eligible full text. Ten articles were extracted into a table and summarized through narrative format. The studies focused on performance-based intervention (60%), cognition (10%), health (10%), occupation (10%), and the environment (10%) in older adult populations (N = 1 - 208); including those with Alzheimer's disease, chronic pain, cancer, and stroke. The interventions were delivered through electronic audio-visual platforms (e.g., zoom) (80%) and teleconference platforms (e.g., phone calls) (20%).

Identifying primary and secondary MLH1 epimutation carriers displaying low-level constitutional MLH1 methylation using droplet digital PCR and genome-wide DNA methylation profiling of colorectal cancers.

BACKGROUND: MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylation and somatic mutational profiles of tumours from two germline MLH1: c.-11C > T and one MLH1: c.-[28A > G; 7C > T] carriers and three MLH1 methylated EOCRCs (< 45 years) were compared with 38 reference CRCs. Methylation-sensitive droplet digital PCR (ddPCR) was used to detect mosaic MLH1 methylation in blood, normal mucosa and buccal DNA. RESULTS: Genome-wide methylation-based Consensus Clustering identified four clusters where the tumour methylation profiles of germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs clustered with the constitutional MLH1 epimutation CRCs but not with the sporadic MLH1 methylated CRCs. Furthermore, monoallelic MLH1 methylation and APC promoter hypermethylation in tumour were observed in both MLH1 epimutation and germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs. Mosaic constitutional MLH1 methylation in MLH1: c.-11C > T carriers and 1 of 3 MLH1 methylated EOCRCs was identified by methylation-sensitive ddPCR. CONCLUSIONS: Mosaic MLH1 epimutation underlies the CRC aetiology in MLH1: c.-11C > T germline carriers and a subset of MLH1 methylated EOCRCs. Tumour profiling and ultra-sensitive ddPCR methylation testing can be used to identify mosaic MLH1 epimutation carriers.

A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome.

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome.

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

Implementation of the CAPABLE Program With Older Adults During the COVID-19 Pandemic.

This study explores the implementation and impact of an evidence-based client-driven program, CAPABLE (Community Aging in Place Advancing Better Living for Elders), during the COVID-19 pandemic. The study reviews outcomes related to client engagement and retainment, client-directed goals, therapeutic intervention, home modifications, and functional outcomes of older adult participants. The CAPABLE program addresses basic and instrumental activities of daily living, medication use, pain, mobility, fall prevention, and environmental modifications within the home. The services were provided by an interprofessional team which included an occupational therapist, a registered nurse, and home contractor professional. The study team utilized descriptive, paired t test, and correlational analyses to evaluate the CAPABLE programs' influence on the functional outcomes of older adults living within the city of St. Louis, during the COVID-19 pandemic. This study identified significant improvement in instrumental activities of daily living (IADLs) independence, readiness to change, self-reported health status, and depressive symptoms, and 11 significant correlations were found between age, implementation expenses, and functional outcomes.

Novel Hybrid Quadrupole-Multireflecting Time-of-Flight Mass Spectrometry System.

A novel mass spectrometry system is described here comprising a quadrupole-multireflecting time-of-flight design. The new multireflecting time-of-flight analyzer has an effective path length of 48 m and employs planar, gridless ion mirrors providing fourth-order energy focusing resulting in resolving power over 200 000 fwhm and sub-ppm mass accuracy. We show how these attributes are maintained with relatively fast acquisition speeds, setting the system apart from other high resolution mass spectrometers. We have integrated this new system into both liquid chromatography-mass spectrometry and mass spectrometry imaging workflows to demonstrate how the instrument characteristics are of benefit to these applications.

'The House of God': reflections 40 years on, in conversation with author Samuel Shem.

The House of God is a seminal work of medical satire based on the gruelling internship experiences of Samuel Shem at the Beth Israel Hospital. Thirteen 'Laws' were offered to rationalise the seemingly chaotic patient management and flow. There have been large shifts in the healthcare landscape and practice since, so we consider whether these medical truisms are still applicable to contemporary National Health Service practice and propose updates where necessary:People are sometimes allowed to die.GOMERs (Get Out of My Emergency Room) still go to ground.Master yourself, join the multidisciplinary team.The patient is the one with the disease, but not the only one suffering.Placement (discharge planning) comes first.There is no body cavity that cannot be reached with a gentle arm and good interventional radiologists.Fit the rule to the patient rather than the patient to the rule.They can always pay you less.The only bad admission is a futile one.If you don't take a temperature you can't find a fever and if you are not going to act on it, don't do the test.Show me a BMS (best medical student) who ONLY triples my work, and I'll show you a future Foundation Year 1 doctor (FY1) who is an asset to the firm.Interpret radiology freely, but share your clinical findings with the radiologist and in a timely fashion.Doing nothing can be a viable option. These were developed in conversation with Samuel Shem, who also offers further insight on the creation of the original laws.

Evaluating case studies of community-oriented integrated care.

This paper summarises a ten-year conversation within London Journal of Primary Care about the nature of community-oriented integrated care (COIC) and how to develop and evaluate it. COIC means integration of efforts for combined disease-treatment and health-enhancement at local, community level. COIC is similar to the World Health Organisation concept of a Community-Based Coordinating Hub - both require a local geographic area where different organisations align their activities for whole system integration and develop local communities for health. COIC is a necessary part of an integrated system for health and care because it enables multiple insights into 'wicked problems', and multiple services to integrate their activities for people with complex conditions, at the same time helping everyone to collaborate for the health of the local population. The conversation concludes seven aspects of COIC that warrant further attention.

Several strategies for clinical partners and universities are perceived to enhance physiotherapy student engagement in non-metropolitan clinical placements: a mixed-methods study.

QUESTION: What strategies can clinical partners and universities implement to enhance physiotherapy student engagement in non-metropolitan clinical placements? DESIGN: Mixed-method research design combining focus groups and survey. PARTICIPANTS: First-year physiotherapy students from one university at the commencement of their course (n=26); third-year and fourth-year students who had completed a non-metropolitan placement (n=39 survey, n=25 focus group); and clinical educators from three non-metropolitan clinical sites (n=15). INTERVENTION: The cohort of first-year physiotherapy students was surveyed to establish their perceptions regarding non-metropolitan clinical education placements. A survey and four focus groups were conducted with third-year and fourth-year students after they had attended non-metropolitan clinical placements, to explore recent experiences. Two focus groups were conducted with clinical educators regarding student engagement at non-metropolitan placements. Quantitative data were summarised with descriptive statistics. Qualitative data were analysed using thematic analysis, synthesising the perspectives of students and clinical educators. RESULTS: At the commencement of their physiotherapy course, interest in undertaking a non-metropolitan clinical placement was higher for students with a non-metropolitan upbringing. Concerns about attending non-metropolitan sites included finances, change in living situation, and perceived inferior quality of clinical education. After completing a non-metropolitan placement, four themes were identified in an analysis of student and educator perceptions: individual factors, clinical experience, logistical challenges and strategies for success. CONCLUSION: Strategies that were perceived to enhance student engagement in non-metropolitan placements included: tailoring preparation for students, paired rather than individual placements, and near-peer presentations for physiotherapy students prior to undertaking non-metropolitan placements. Dedicated clinical coordinator positions at non-metropolitan sites and assistance in accessing affordable accommodation are likely to positively influence the student experience. [Francis-Cracknell A, Maver S, Kent F, Edwards E, Iles R (2017) Several strategies for clinical partners and universities are perceived to enhance physiotherapy student engagement in non-metropolitan clinical placements: a mixed-methods study. Journal of Physiotherapy 63: 243-249].

Population trends in the 10-year incidence and prevalence of diabetic retinopathy in the UK: a cohort study in the Clinical Practice Research Datalink 2004-2014.

OBJECTIVES: To describe trends in the incidence and prevalence of diabetic retinopathy (DR) in the UK by diabetes type, age, sex, ethnicity, deprivation, region and calendar year. DESIGN: Cohort study using the Clinical Practice Research Datalink (CPRD). SETTING: UK primary care. PARTICIPANTS: 7.7 million patients ≥12 contributing to the CPRD from 2004 to 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: Age-standardised prevalence and incidence of diabetes, DR and severe DR (requiring photocoagulation) by calendar year and population subgroup. Relative risk of developing DR and severe DR by population subgroup. RESULTS: The prevalence of DR was 48.4% in the population type 1 diabetes mellitus (T1DM) (14 846/30 657) and 28.3% (95 807/338 390) in the population with type 2 diabetes mellitus (T2DM). Prevalence of DR remained stable in people with T2DM and decreased in people with T1DM. Screening for DR increased over time for patients with T2DM and remained static for patients with T1DM Incidence of DR increased in parallel with the incidence of T2DM in both diabetic populations. Among patients with T2DM, relative risk of DR varied significantly by region, was increased for older age groups and in men compared with women, with risk of severe DR increased in South Asian groups and more deprived groups. Relative risk of DR for patients with T1DM varied by age and region, but not by gender, ethnic group or deprivation. CONCLUSIONS: This is the largest study to date examining the burden of DR in the UK. Regional disparities in incidence may relate to differences in screening delivery and disease ascertainment. Evidence that deprivation and ethnicity are associated with a higher risk of severe DR highlights a significant potential health inequality. Findings from this study will have implications for professionals working in the diabetes and sight loss sectors, particularly to inform approaches for diagnosis of retinopathy and campaigning to better tackle the disease for at risk groups.