Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation.

The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage. Herein, we report the realization of this approach through the conversion of aliphatic alcohols into the corresponding difluoromethylated analogues via the merger of benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)-CF2H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Why don't women engage in muscle strength exercise? An integrative review.

ISSUE ADDRESSED: Women are 'at-risk' population for failing to meet muscle strengthening guidelines. Health benefits specific to this exercise mode include maintenance of muscle mass, which is associated with reduced risk of chronic disease and falls. Of significance is the progressive decline in muscle strength exercise participation in women aged 35-54 in Australia. This period is critical for maintaining muscle strength as it establishes foundations for older women's engagement. This integrative review examined available evidence regarding factors influencing muscle strength exercise participation, specifically in women aged 35-54. METHODS: Seven databases were searched. Study inclusion criteria were: (1) peer reviewed, (2) English language, (3) sample populations of healthy female adults or general adult sample population differentiating females from males, (4) mean age between 35 and 54 years, (5) focused on muscle strength exercise and measured as the primary outcome factors of participation in muscle strength exercise. FINDINGS: Five of 1895 studies met inclusion criteria. Five key factors were associated with participation in muscle strength exercise of women aged 35-54 years: perceived time constraints; knowledge and education; modality and intensity; social support and behavioural strategies. CONCLUSIONS: Focused education on strength exercise and guidelines, plus initiatives and strategies that suit the needs of this cohort, are necessary to achieve health and wellbeing benefits. Responsive approaches by health professionals to these women's circumstances can potentially address current low participation levels. SO WHAT?: Creating conditions where health professionals respect a woman's exercise preferences can positively impact these women's musculoskeletal health into older age.

Behaviour regulation and the role of mental health in non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in wealthy societies, and is responsible for a significant rise in liver morbidity and mortality. Current treatments prioritise lifestyle interventions, predominantly diet and exercise management, but patients frequently fail to make the necessary behavioural adjustments. The current study seeks to identify those factors which influence patients' behaviour with respect to adherence to treatment regimes. METHODS: Novel areas of interest were investigated; locus of control, behavioural regulation and a range of mental health measures, due to their links to either poor lifestyle choices or abnormal eating as identified in previous literature. Data was gathered using self-report questionnaires, from 96 participants, who were split into three groups, NAFLD patients, non-NAFLD liver disease patients and healthy controls RESULTS: Data was analysed using a MANOVA, and followed up with a Tukey post-hoc test. Three factors were found to be significant by group; cognitive restraint, uncontrolled eating and SAPAS score (a measure of personality disorders). An association between personality disorders and NAFLD was identified. CONCLUSION: It is suggested that NAFLD patients are screened for personality disorders and, if identified, treated prior to the commencement of diet and exercise management.

Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp3)-C(sp3) Cross-Coupling via Radical Sorting.

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, and the resulting open-shell intermediates can subsequently participate in transition metal catalysis. In this report, we describe the C(sp3)-C(sp3) cross-coupling of alcohols and carboxylic acids through the dual combination of N-heterocyclic carbene (NHC)-mediated deoxygenation and hypervalent iodine-mediated decarboxylation. This mild and practical Ni-catalyzed radical-coupling protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products, including highly congested quaternary carbon centers from the corresponding tertiary alcohols or tertiary carboxylic acids. We demonstrate the synthetic applications of this methodology to alcohol C1-alkylation and formal homologation, as well as to the late-stage functionalization of drugs, natural products, and biomolecules.

Alcohols as Alkylating Agents: Photoredox-Catalyzed Conjugate Alkylation via In Situ Deoxygenation.

The rapid exploration of sp3 -enriched chemical space is facilitated by fragment-coupling technologies that utilize simple and abundant alkyl precursors, among which alcohols are a highly desirable, commercially accessible, and synthetically versatile class of substrate. Herein, we describe an operationally convenient, N-heterocyclic carbene (NHC)-mediated deoxygenative Giese-type addition of alcohol-derived alkyl radicals to electron-deficient alkenes under mild photocatalytic conditions. The fragment coupling accommodates a broad range of primary, secondary, and tertiary alcohol partners, as well as structurally varied Michael acceptors containing traditionally reactive sites, such as electrophilic or oxidizable moieties. We demonstrate the late-stage diversification of densely functionalized molecular architectures, including drugs and biomolecules, and we further telescope our protocol with metallaphotoredox cross-coupling for step-economic access to sp3 -rich complexity.

Identifying dementia in Down syndrome with the Severe Impairment Battery, Brief Praxis Test and Dementia Scale for People with Learning Disabilities.

BACKGROUND: Individuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer's disease. However, many measures regularly used for the detection of dementia in the general population are not suitable for individuals with DS due in part to floor effects. Some measures, including the Severe Impairment Battery (SIB), Brief Praxis Test (BPT) and Dementia Scale for People with Learning Disabilities (DLD), have been used in clinical trials and other research with this population. Validity research is limited, particularly regarding the use of such tools for detection of prodromal dementia in the DS population. The current project presents baseline cross-sectional SIB, BPT and DLD performance in order to characterise their predictive utility in discriminating normal cognition, possible dementia and probable dementia in adult DS. METHOD: Baseline SIB, BPT and DLD performances from 100 individuals (no dementia = 68, possible dementia = 16 & probable dementia = 16) were examined from a longitudinal cohort of aging individuals with DS. Receiver operating characteristic curves investigated the accuracy of these measures in relation to consensus dementia diagnoses, diagnoses which demonstrated high percent agreement with the examining neurologist's independent diagnostic impression. RESULTS: The SIB and BPT exhibited fair discrimination ability for differentiating no/possible versus probable dementia [area under the curve (AUC) = 0.61 and 0.66, respectively]. The DLD exhibited good discrimination ability for differentiating no versus possible/probable dementia (AUC = 0.75) and further demonstrated better performance of the DLD Cognitive subscale compared with the DLD Social subscale (AUC = 0.77 and 0.67, respectively). CONCLUSIONS: Results suggest that the SIB, BPT and DLD are able to reasonably discriminate consensus dementia diagnoses in individuals with DS, supporting their continued use in the clinical assessment of dementia in DS. The general performance of these measures suggests that further work in the area of test development is needed to improve on the AUCs for dementia status discrimination in this unique population. At present, however, the current findings suggest that the DLD may be the best option for reliable identification of prodromal dementia in this population, reinforcing the importance of including informant behaviour ratings in assessment of cognition for adults with DS.

Cross-Electrophile Coupling of Unactivated Alkyl Chlorides.

Alkyl chlorides are bench-stable chemical feedstocks that remain among the most underutilized electrophile classes in transition metal catalysis. Overcoming intrinsic limitations of C(sp3)-Cl bond activation, we report the development of a novel organosilane reagent that can participate in chlorine atom abstraction under mild photocatalytic conditions. In particular, we describe the application of this mechanism to a dual nickel/photoredox catalytic protocol that enables the first cross-electrophile coupling of unactivated alkyl chlorides and aryl chlorides. Employing these low-toxicity, abundant, and commercially available organochloride building blocks, this methodology allows access to a broad array of highly functionalized C(sp2)-C(sp3) coupled adducts, including numerous drug analogues.

A preliminary study of cerebral blood flow, aging and dementia in people with Down syndrome.

BACKGROUND: People with Down syndrome (DS) develop Alzheimer's disease (AD) at an earlier age of onset than those with sporadic AD. AD neuropathology is typically present in DS by 40 years of age with an onset of dementia approximately 10 years later. This early onset is due to the overexpression of amyloid precursor protein from the third copy of chromosome 21. Cerebrovascular neuropathology is thought to contribute in 40-60% of cases sporadic AD. However, the vascular contribution to dementia in people with DS has been relatively unexplored. We hypothesised that vascular perfusion is compromised in older adults with DS relative to younger individuals and is further exacerbated in those with dementia. METHOD: Cerebral blood flow (CBF) was measured using pulsed arterial spin labelling in 35 cognitively characterised adults with DS (26-65 years). DS participants were also compared with 15 control subjects without DS or dementia (26-65 years). Linear regression evaluated the difference in CBF across groups and diagnosis along with assessing the association between CBF and cognitive measures within the DS cohort. RESULTS: Cerebral blood flow was significantly lower among DS participants with probable AD compared with controls (P = 0.02) and DS participants with no dementia (P = 0.01). Within the DS cohort, CBF was significantly associated with the Severe Impairment Battery (SIB) measure and the Dementia Questionnaire for People with Learning Disabilities (DLD) rating (F3,25  = 5.13; P = 0.007). Both the SIB (ß = 0.74; t = 2.71; P = 0.01) and DLD (ß = -0.96; t = -3.87; P < 0.001) indicated greater impairment as global CBF decreased. Age was significantly associated with CBF among participants with DS. There was a non-linear effect of age, whereby CBF declined more rapidly after 45 years of age. CONCLUSIONS: This preliminary study of CBF in DS indicates that cerebrovascular pathology may be a significant contributor to dementia in DS. CBF was associated with diagnosis, cognition and age. Notably, CBF decreases at a greater rate after age 45 and may represent a significant prodromal event in AD progression.

Pressure densified 1,3,5-tri(1-naphthyl)benzene glass. I. Volume recovery and physical aging.

The effects of pressure densification on 1,3,5-tri(1-naphthyl)benzene (TNB) are assessed from volumetric and calorimetric measurements. The pressure densified glass (PDG) has higher density than conventional glass (CG), but unlike ultrastable TNB glass prepared using vapor deposition which also has elevated density, TNB PDG exhibits higher enthalpy and lower thermal stability than when formed at ambient pressure. PDG also exhibits anomalous physical aging. Rather than evolving monotonically toward the equilibrium density, there is an overshoot to a lower density state. Only when the density of the PDG becomes equivalent to the corresponding CG does the density begin a slow approach toward equilibrium.

Exploiting the Marcus inverted region for first-row transition metal-based photoredox catalysis.

Second- and third-row transition metal complexes are widely employed in photocatalysis, whereas earth-abundant first-row transition metals have found only limited use because of the prohibitively fast decay of their excited states. We report an unforeseen reactivity mode for productive photocatalysis that uses cobalt polypyridyl complexes as photocatalysts by exploiting Marcus inverted region behavior that couples increases in excited-state energies with increased excited-state lifetimes. These cobalt (III) complexes can engage in bimolecular reactivity by virtue of their strong redox potentials and sufficiently long excited-state lifetimes, catalyzing oxidative C(sp2)-N coupling of aryl amides with challenging sterically hindered aryl boronic acids. More generally, the results imply that chromophores can be designed to increase excited-state lifetimes while simultaneously increasing excited-state energies, providing a pathway for the use of relatively abundant metals as photoredox catalysts.

Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury.

Donation after cardiac death (DCD) liver transplantation is associated with an increased frequency of hepato-biliary complications. The implications for renal function have not been explored previously. The aims of this single-center study of 88 consecutive DCD liver transplant recipients were (1) to compare renal outcomes with propensity-risk-matched donation after brain death (DBD) patients and (2) in the DCD patients specifically to examine the risk factors for acute kidney injury (AKI; peak creatinine ≥2 times baseline) and chronic kidney disease (CKD; eGFR <60 mL/min/1.73 m(2) ). During the immediate postoperative period DCD liver transplantation was associated with an increased incidence of AKI (DCD, 53.4%; DBD 31.8%, p = 0.004). In DCD patients AKI was a risk factor for CKD (p = 0.035) and mortality (p = 0.017). The cumulative incidence of CKD by 3 years post-transplant was 53.7% and 42.1% for DCD and DBD patients, respectively (p = 0.774). Importantly, increasing peak perioperative aspartate aminotransferase, a surrogate marker of hepatic ischemia reperfusion injury, was the only consistent predictor of renal dysfunction after DCD transplantation (AKI, p < 0.001; CKD, p = 0.032). In conclusion, DCD liver transplantation is associated with an increased frequency of AKI. The findings suggest that hepatic ischemia reperfusion injury may play a critical role in the pathogenesis of post-transplant renal dysfunction.

Environmental sampling of innate hospital surfaces: a survey of current practices and the need for guidelines.

BACKGROUND: Surfaces in healthcare facilities can act as reservoirs of infection. Currently, no standardized protocol on when and how to sample hospital surfaces exists. AIM: A web-based questionnaire was devised to gain insight into current sampling practices and was distributed by email to a targeted infection prevention and control (IPC) audience. METHODS: The survey consisted of 26 questions on sample collection and processing for a number of healthcare relevant bacterial species. FINDINGS: The majority of respondents were clinical microbiologists or IPC practitioners, and 57.3% were from either the Netherlands, the United Kingdom, or Ireland. Respondents had high self-reported knowledge, but this was not consistent with response to certain questions. There was no consensus on sample sites, either within or between countries. Indirect sampling methods were preferred for all target microorganisms, and cotton and flocked swabs were the most popular methods. CONCLUSION: The results of our survey highlight the inconsistencies in environmental sampling between and within countries, and the need for guidance and consensus.

Obesity bias and stigma, attitudes and beliefs among entry-level physiotherapy students in the Republic of Ireland: a cross sectional study.

OBJECTIVE: To explore entry-level physiotherapy students' attitudes and beliefs relating to weight bias and stigmatisation in healthcare. DESIGN: Cross sectional survey of physiotherapy students. METHODS: All final year physiotherapy students (n = 215) enrolled in entry-level physiotherapy programmes in the Republic of Ireland were invited to participate. Each received a questionnaire, consisting of 72 questions, within four key sections. Descriptive statistics and frequencies were used to analyse the data. RESULTS: A response rate of 83% (179/215) was achieved. Whilst physiotherapy students, overall, had a positive attitude towards people with obesity, 29% had a negative attitude towards people with obesity, 24% had a negative attitude towards managing this population and most (74%) believed obesity was caused by behavioural and individual factors. Over one third of students (35%) reported that they would not be confident in managing patients with obesity and more than half (54%) felt treating patients with obesity was not worthwhile. CONCLUSION: This study provides preliminary findings to suggest that weight stigma-reduction efforts are warranted for physiotherapy students. Helping students to understand that obesity is a complex, chronic condition with multiple aspects requiring a multi-faceted approach to its management might be the first step towards dispelling these negative attitudes towards patients living with obesity. Inclusion of a formal obesity curriculum should perhaps now be part of the contemporary physiotherapy students' education.

The daily direct costs of isolating patients identified with highly resistant micro-organisms in a non-outbreak setting.

BACKGROUND: Isolation precautions are recommended when caring for patients identified with highly resistant micro-organisms (HRMOs). However, the direct costs of patients in isolation are largely unknown. AIM: To obtain detailed information on the daily direct costs associated with isolating patients identified with HRMOs. METHODS: This study was performed from November until December 2017 on a 12-bed surgical ward. This ward contained solely isolation rooms with anterooms. The daily direct costs of isolation were based on three cost items: (1) additional personal protective equipment (PPE), measured by counting the consumption of empty packaging materials; (2) cleaning and disinfection of the isolation room, based on the costs of an outsourced cleaning company; and (3) additional workload for healthcare workers, based on literature and multiplied by the average gross hourly salary of nurses. A distinction was made between the costs for strict isolation, contact-plus isolation, and contact isolation. FINDINGS: During the study period, 26 patients were nursed in isolation because of HRMO carriage. Time for donning and doffing of PPE was 31 min per day. The average daily direct costs of isolation were the least expensive for contact isolation (gown, gloves), €28/$31, and the most expensive for strict isolation (surgical mask, gloves, gown, cap), €41/$47. CONCLUSION: Using a novel, easy method to estimate consumption of PPE, we conclude that the daily direct costs of isolating a patient differ per type of isolation. Insight into the direct costs of isolation is of utmost importance when developing or updating infection prevention policies.

Identifying ecological production functions for use in ecosystem services-based environmental risk assessment of chemicals.

There is increasing research interest in the application of the ecosystem services (ES) concept in the environmental risk assessment of chemicals to support formulating and operationalising regulatory environmental protection goals and making environmental risk assessment more policy- and value-relevant. This requires connecting ecosystem structure and processes to ecosystem function and henceforth to provision of ecosystem goods and services and their economic valuation. Ecological production functions (EPFs) may help to quantify these connections in a transparent manner and to predict ES provision based on function-related descriptors for service providing species, communities, ecosystems or habitats. We review scientific literature for EPFs to evaluate availability across provisioning and regulation and maintenance services (CICES v5.1 classification). We found quantitative production functions for nearly all ES, often complemented with economic valuation of physical or monetary flows. We studied the service providing units in these EPFs to evaluate the potential for extrapolation of toxicity data for test species obtained from standardised testing to ES provision. A broad taxonomic representation of service providers was established, but quantitative models directly linking standard test species to ES provision were extremely scarce. A pragmatic way to deal with this data gap would be the use of proxies for related taxa and stepwise functional extrapolation to ES provision and valuation, which we conclude possible for most ES. We suggest that EPFs may be used in defining specific protection goals (SPGs), and illustrate, using pollination as an example, the availability of information for the ecological entity and attribute dimensions of SPGs. Twenty-five pollination EPFs were compiled from the literature for biological entities ranging from 'colony' to 'habitat', with 75% referring to 'functional group'. With about equal representation of the attributes 'function', 'abundance' and 'diversity', SPGs for pollination therefore would seem best substantiated by EPFs at the level of functional group.

Differential effect of isotype on efficacy of anti-tumor necrosis factor alpha chimeric antibodies in experimental septic shock.

Immune complexes containing human gamma (g)1 or murine g2a antibodies generate secondary effector mechanisms via Fc receptor binding or complement activation, whereas those containing human g4 or murine g1 antibodies generally do not. Therefore, isotype selection of therapeutic antibodies may have important clinical consequences. In a rabbit model of human tumor necrosis factor (rhuTNF)-induced pyrexia, a murine/human chimeric g4 anti-human TNF-alpha monoclonal antibody (mAb) (cCB0011) showed a dose-dependent inhibition of pyrexia, whereas a g1 isotype variant of the same mAb gave a marked pyrexia that was seen at all doses indicative of an immune complex-mediated response. To investigate whether isotype difference could influence mAb efficacy in pathological disease states, hamster/murine chimeric g1 and g2a anti-murine TNF-alpha mAbs (TN3g1, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatment with TN3g1 mAb at 30 and 3 mg/kg resulted in 90% survival by 72 h (p < or = 0.004), and prolonged survival to 45 h (p < or = 0.05), respectively, compared with 100% mortality by 27 h in controls. In contrast, a g2a isotype variant of the same mAb (30 mg/kg) resulted in only 10% survival by 72 h (p < or = 0.05). In a neutropenic sepsis model in rats there was greater survival in animals receiving the g1 isotype of TN3 compared with g2a isotype variant (70 vs. 27%; p < or = 0.005) with 100% mortality in the controls. These differences were not due to the pharmacokinetic profiles of the mAbs. In models of experimental shock antibody isotype can affect outcome with inactive isotypes (human g4 and murine g1) being more efficacious than active isotypes (human g1 and murine g2a).

Emergency department attendance by children at risk of abuse.

BACKGROUND: Frequency of emergency department (ED) attendance has long been thought to be a risk factor for child abuse. The aim of this study was to test this assumption by comparing the ED attendances of at-risk children (before being placed on a child protection register) with the attendances of an age-matched control group (before an index attendance) Method: A group of 220 children (aged 0-12 years inclusive) were identified from the two child protection registers in the Shropshire area in 2006. The ED attendances of these children in the 2 years before registration were identified using the computer records of the two local EDs. A control group of 150 children for each year of age (0-12 years inclusive) was then identified from ED attendances between October and December 2006. The attendances of these children in the 2 years before this index attendance were obtained. The data for these two groups of children were then compared. RESULTS: The at-risk children did not attend the EDs more frequently than did the children in the control group. CONCLUSION: The identification of children who attend EDs frequently may be useful for other reasons but is unlikely to be an effective way to detect child abuse.

Dynamic Properties of Supercooled Chlorinated Biphenyls.

A study of the dynamics of a series of biphenyl compounds having varying chlorine levels was carried out. Increasing the chlorine content increases the glass transition temperature and makes the dynamics substantially more sensitive to density changes. Nonetheless, in the vicinity of their respective glass transitions, the different liquids display very similar extents of dynamic correlation and dynamic heterogeneity. The slight narrowing of the relaxation peak with increasing chlorine follows the general trend of the effect of increasing molecular polarity. This relationship between the peak breadth and dipole moment was reproduced in molecular dynamics simulations of a simplified model of the Aroclor molecule.