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Background: Special low-protein foods are essential in the dietary treatment of phenylketonuria (PKU). In the UK, these are available on prescription through the General Practitioners (GPs) and distributed via nutritional home delivery companies or pharmacies., Methods: A 58-item online non-validated semi-structured questionnaire was emailed to British Inherited Metabolic Disease Group (BIMDG) dietitians and dietetic support workers (DSW)/administrators working in PKU to ascertain the main system issues and errors with the supply of low-protein prescription foods (LPPF)., Results: 73% ( n = 53/73) of dietitians and 72% ( n = 18/25) of DSW/administrators responded. A total of 80 questionnaires (representing 44 paediatric and 36 adult PKU centres) were completed. A total of 50% ( n = 40/80) of respondents reported patient/caregiver problems accessing LPPF at least weekly. The most common problems were unavailable products (82%), missing LPPF in deliveries (79%), and delayed deliveries (66%). For 64% of respondents, >25% of their patients had recurring problems accessing LPPF, and 69% of respondents spent ≥1 h/week and 11% >5 h/week correcting LPPF patient supply issues. The most common foods patients experienced supply issues with were bread (96%), pasta/rice (41%) and milk replacements (35%). This was associated with GP prescription errors (65%), LPPF prescriptions sent to incorrect dispensers/suppliers (60%), and manufacturer supply issues (54%). Problems with patients/caregivers included not ordering LPPF in a timely way (81%), not responding to messages from home delivery companies (73%) and poor understanding of the ordering process (70%). The majority (93%) of respondents reported that prescription issues impacted their patients' blood Phe control. Suggestions for improving access to LPPF included centralisation of the system to one supplier (76%) and apps for ordering LPPF (69%)., Conclusions: The supply of LPPF for PKU in the UK is problematic; it may adversely affect the ability of patients to adhere to dietary management, and a review investigating patient access to LPPF is urgently required.

Introduction: There is little practical guidance about suitable food choices for higher natural protein tolerances in patients with phenylketonuria (PKU). This is particularly important to consider with the introduction of adjunct pharmaceutical treatments that may improve protein tolerance. Aim: To develop a set of guidelines for the introduction of higher protein foods into the diets of patients with PKU who tolerate >10 g/day of protein. Methods: In January 2022, a 26-item food group questionnaire, listing a range of foods containing protein from 5 to >20 g/100 g, was sent to all British Inherited Metabolic Disease Group (BIMDG) dietitians (n = 80; 26 Inherited Metabolic Disease [IMD] centres). They were asked to consider within their IMD dietetic team when they would recommend introducing each of the 26 protein-containing food groups into a patient’s diet who tolerated >10 g to 60 g/day of protein. The patient protein tolerance for each food group that received the majority vote from IMD dietetic teams was chosen as its tolerance threshold for introduction. A virtual meeting was held using Delphi methodology in March 2022 to discuss and agree final consensus. Results: Responses were received from dietitians from 22/26 IMD centres (85%) (11 paediatric, 11 adult). For patients tolerating protein ≥15 g/day, the following foods were agreed for inclusion: gluten-free pastas, gluten-free flours, regular bread, cheese spreads, soft cheese, and lentils in brine; for protein tolerance ≥20 g/day: nuts, hard cheeses, regular flours, meat/fish, and plant-based alternative products (containing 5−10 g/100 g protein), regular pasta, seeds, eggs, dried legumes, and yeast extract spreads were added; for protein tolerance ≥30 g/day: meat/fish and plant-based alternative products (containing >10−20 g/100 g protein) were added; and for protein tolerance ≥40 g/day: meat/fish and plant-based alternatives (containing >20 g/100 g protein) were added. Conclusion: This UK consensus by IMD dietitians from 22 UK centres describes for the first time the suitability and allocation of higher protein foods according to individual patient protein tolerance. It provides valuable guidance for health professionals to enable them to standardize practice and give rational advice to patients.

Patients with phenylketonuria (PKU) are reliant on special low protein foods (SLPFs) as part of their dietary treatment. In England, several issues regarding the accessibility of SLPFs through the national prescribing system have been highlighted. Therefore, prescribing patterns and expenditure on all SLPFs available on prescription in England ( n = 142) were examined. Their costs in comparison to regular protein-containing ( n = 182) and 'free-from' products ( n = 135) were also analysed. Similar foods were grouped into subgroups ( n = 40). The number of units and costs of SLPFs prescribed in total and per subgroup from January to December 2020 were calculated using National Health Service (NHS) Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool) for England. Monthly patient SLPF units prescribed were calculated using patient numbers with PKU and non-PKU inherited metabolic disorders (IMD) consuming SLPFs. This was compared to the National Society for PKU (NSPKU) prescribing guidance. Ninety-eight percent of SLPF subgroups ( n = 39/40) were more expensive than regular and 'free-from' food subgroups. However, costs to prescribe SLPFs are significantly less than theoretical calculations. From January to December 2020, 208,932 units of SLPFs were prescribed (excluding milk replacers), costing the NHS £2,151,973 (including milk replacers). This equates to £962 per patient annually, and prescribed amounts are well below the upper limits suggested by the NSPKU, indicating under prescribing of SLPFs. It is recommended that a simpler and improved system should be implemented. Ideally, specialist metabolic dietitians should have responsibility for prescribing SLPFs. This would ensure that patients with PKU have the necessary access to their essential dietary treatment, which, in turn, should help promote dietary adherence and improve metabolic control.

What prevents the delivery of effective, high quality and safe health care in the National Health Service (NHS) in England? This paper presents 760 challenges which 330 NHS staff reported as preventing the delivery of effective, high quality and safe care. Some problems have been known for over 25 years (staff shortages, finance and patient complexity) but other challenges raise questions about the commitment of the NHS to patient and staff safety. For example, Organisational Culture leading to 'stifling bureaucracy', 'odds stacked against smooth […] working' and Workload resulting in 'firefighting daily' and 'perpetual crisis mode'. The role of Human Factors/Ergonomics professional input (engagement with safety scientists) is discussed in the context of success stories and examples of Human Factors Integration from other safety critical industries (Defence, Nuclear and Rail). Practitioner Summary: 760 challenges to the quality, effectiveness and safety of health care were identified at Human Factors/Ergonomics taster workshops in England. These are used to challenge health care providers to think about a Human Factors Integration (HFI systems) approach for safety, well-being and performance for all people involved in providing and receiving health care.

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 μM., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibitor PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of ≥0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.

Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype., (2010 Elsevier Ltd. All rights reserved.)

A group performance test of handedness was administered to 1556 undergraduates. This test required subjects to place dots in circles as rapidly as possible. The test was found to be reliable, and to correlate with hand preference. Both hand performance and hand preference measures are skewed in the population as a whole, but the distributions can be adequately fitted by two normal curves, one with a right bias and one with a left bias. These findings suggest that left-handers are a distinct subgroup of the population.

Right-handers who write with an inverted writing posture (N = 8) were compared to right-handers who write in the normal fashion (N = 16) on tests of handedness and hemispheric asymmetry. Inverted writers showed the same laterality effects as normal writers for dot location and the recognition of visually-presented nonsense syllables. In dichotic listening, inverted writers were much more likely to show a left-ear superiority than were normal writers. They also were more strongly right-handed on a speeded performance test, but not in hand preference. This pattern is quite different from that obtained with left-handers, and suggests that the inverting handwriting posture has a different basis in right-handers than in left-handers.