Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides.

The nature of the first genetic polymer is the subject of major debate1. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life2,3-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA4. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life5.

Prebiotic Synthesis of N-Formylaminonitriles and Derivatives in Formamide.

Amino acids and their derivatives were probably instrumental in the transition of prebiotic chemistry to early biology. Accordingly, amino acid formation under prebiotic conditions has been intensively investigated. Unsurprisingly, most of these studies have taken place with water as the solvent. Herein, we describe an investigation into the formation and subsequent reactions of aminonitriles and their formylated derivatives in formamide. We find that N-formylaminonitriles form readily from aldehydes and cyanide in formamide, even in the absence of added ammonia, suggesting a potentially prebiotic source of amino acid derivatives. Alkaline processing of N-formylaminonitriles proceeds with hydration at the nitrile group faster than deformylation, protecting aminonitrile derivatives from reversion of the Strecker condensation equilibrium during hydration/hydrolysis and furnishing mixtures of N-formylated and unformylated amino acid derivatives. Furthermore, the facile synthesis of N-formyldehydroalanine nitrile is observed in formamide from glycolaldehyde and cyanide without intervention. Dehydroalanine derivatives have been proposed as important compounds for prebiotic peptide synthesis, and we demonstrate both a synthesis suggesting that they are potentially plausible components of a prebiotic inventory, and reactions showing their utility as abiotic precursors to a range of compounds of prebiological interest.

A biomechanical analysis of double-screw, double-button, and screw-button fixation constructs in patient-specific instrument-guided Latarjet procedure.

BACKGROUND: The Latarjet coracoid transfer procedure reliably stabilizes the glenohumeral joint for shoulder instability. However, complications such as graft osteolysis, nonunion and fracture continue to affect patient clinical outcomes. The double-screw (SS) construct is regarded as the gold standard method of fixation. SS constructs are associated with graft osteolysis. More recently, a double-button technique (BB) has been suggested to minimize graft-related complications. However, BB constructs are associated with fibrous nonunion. To mitigate this risk, a single screw combined with a single button (SB) construct has been proposed. It is thought that this technique incorporates the strength of the SS construct and allows micromotion superiorly to mitigate stress shielding-related graft osteolysis. AIMS: The primary aim of this study was to compare the failure load of SS, BB, and SB constructs under a standardized biomechanical loading protocol. The secondary aim was to characterize the displacement of each construct throughout testing. METHODS: Computed tomography scans of 20 matched-pair cadaveric scapulae were performed. Specimens were harvested and dissected free of soft tissue. SS and BB techniques were randomly assigned to specimens for matched-pair comparison with SB trials. A patient-specific instrument (PSI)-guided Latarjet procedure was performed on each scapula. Specimens were tested using a uniaxial mechanical testing device under cyclic loading (100 cycles, 1 Hz, 200 N/s) followed by a load-to-failure protocol (0.5 mm/s). Construct failure was defined by graft fracture, screw avulsion, and/or graft displacement of more than 5 mm. RESULTS: Forty scapulae from 20 fresh frozen cadavers with a mean age of 69.3 years underwent testing. On average, SS constructs failed at 537.8 N (SD 296.8), whereas BB constructs failed at 135.1 N (SD 71.4). SB constructs required a significantly greater load to fail compared with BB constructs (283.5 N, SD 162.8, P = .039). Additionally, SS (1.9 mm, IQR 0.87) had a significantly lower maximum total graft displacement during the cyclic loading protocol compared with SB (3.8 mm, IQR 2.4, P = .007) and BB (7.4 mm, IQR 3.1, P < .001) constructs. CONCLUSION: These findings support the potential of the SB fixation technique as a viable alternative to SS and BB constructs. Clinically, the SB technique could reduce the incidence of loading-related graft complications seen in the first 3 months of BB Latarjet cases. The study is limited to time-specific results and does not account for bone union or osteolysis.

Safety and usability of proning pillows in intensive care: A scoping review.

OBJECTIVES: Proning is an established technique for the care of intubated patients with severe respiratory failure. Positioning devices used to support the head and body of patients placed in the prone position are often associated with the formation of pressure injuries. Despite robust literature on the prevention and monitoring of pressure injuries, little is described about the role of proning pillows on pressure injuries. The objective of this review is to understand the extent of evidence pertaining to the safety and usability of different types of proning pillows in the intensive care setting. REVIEW METHOD: A scoping review of the literature was completed using predefined search terms in three databases and identified 296 articles. An additional 26 were included from reference lists. Twenty studies are included in the analysis; most were published in the past 3 years, with >50% in surgical settings. DATA SOURCES: Three databases were searched: PubMed, Scopus, and EMBASE. REVIEW METHODS: The review followed the PRISMA Extension for Scoping Reviews, and data were reviewed using Covidence. RESULTS: The most prevalent proning pillow is a standard, noncontoured foam head positioner. It is responsible for the majority of facial pressure injuries in all settings of care. Memory foam pillows and helmet-based systems offer improved surface pressure distribution, although their usability in the intensive care setting remains poorly studied. Inflatable air-cell-based devices present an alternative, but the lack of supporting research and the costs may explain their poor uptake. Several articles proposed the use of pressure sensor systems to evaluate devices. We propose a set of ergonomic parametres to consider when choosing or designing a positioning device for proned patients. CONCLUSION: The evidence pertaining to the safety and usability of proning pillows in the intensive care setting is scarce, which provides opportunities for future research to improve the efficacy in the prevention of pressure injuries and the user experience.

Illuminating Life's Origins: UV Photochemistry in Abiotic Synthesis of Biomolecules.

Solar radiation is the principal source of energy available to Earth and has unmatched potential for the synthesis of organic material from primordial molecular building blocks. As well as providing the energy for photochemical synthesis of (proto)biomolecules of interest in origins of life-related research, light has also been found to often provide remarkable selectivity in these processes, for molecules that function in extant biology and against those that do not. As such, light is heavily implicated as an environmental input on the nascent Earth that was important for the emergence of complex yet selective chemical systems underpinning life. Reactivity and selectivity in photochemical prebiotic synthesis are discussed, as are their implications for origins of life scenarios and their plausibility, and the future directions of this research.

Prebiotic Photochemical Coproduction of Purine Ribo- and Deoxyribonucleosides.

The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2'-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.

Computed tomographic evaluation of glenoid joint line restoration with glenoid bone grafting and reverse shoulder arthroplasty in patients with significant glenoid bone loss.

BACKGROUND: Restoration of native glenohumeral joint line is important for a successful outcome after reverse shoulder arthroplasty (RSA). The aims of this study were to quantify the restoration of glenoid joint line after structural bone grafting and RSA, and to evaluate graft incorporation, correction of glenoid version, and rate of notching. METHODS: This is a retrospective review of 21 patients who underwent RSA (20 primary, 1 revision) with glenoid bone grafting (15 autografts, 6 allografts). Grammont design implants and baseplate with long peg were used in all patients. Preoperative and postoperative 3D models were created using MIMICS 21.0. Preoperative defects were classified, and postoperative joint line restoration was assessed based on the lateral aspect of the base of the coracoid. Postoperative computed tomographic (CT) scans were evaluated for graft incorporation, version correction, and presence of notching. RESULTS: Preoperative glenoid defects were classified as massive (5%), large (29%), moderate (52%), and small (14%). The average preoperative version was 8° of retroversion. The average postoperative version was 5° of retroversion. The average preoperative medialization was noted to be 8.4 mm medial to native joint line or 0.6 mm (range -16.8 to 13.2) lateral to the coracoid base. The postoperative CT scans demonstrated a mean joint line at 12.1 mm (range 1.3-22.4) lateral to the coracoid base. At the 3-month follow-up, all patients demonstrated graft incorporation on CT scans. Graft osteolysis was observed on CT scan in 4.8% of patients at a mean follow-up of 19.5 months. DISCUSSION: Structural bone grafting of glenoid defect effectively re-creates the glenoid anatomy, restores glenoid bone stock, re-creates the true glenohumeral joint line, and corrects glenoid deformity. The use of bone grafting also allows lateralization of the baseplate and glenosphere, reducing the risk of severe scapular notching. CONCLUSION: Restoration of the glenoid joint line was achieved in all patients. Glenoid bone grafting is a viable option for restoring glenoid joint line in cases of significant glenoid defects encountered during RSA.

On the approximation of independent pairs in diffusion kinetics: correlation of distances in a three-body system.

This study investigates the problem of diffusion kinetics in a three-body system, motivated by the theory of radiation chemical kinetics. The backward diffusion equation for the joint density of the distances is formulated, and an explicit formula for the infinitesimal covariance of two diffusing distances is derived. The Clifford-Green theorem is used to show how the infinitesimal covariance of two distances is linked to the covariance of the corresponding two squared distances as time evolves. In addition, computer simulations for the problem are presented, which indicate that hitting probabilities are also correlated. While the results indicate that more work is needed before a usable correction to the independence approximation is possible, clear progress has been made.

Bio-inspired Domino oxa-Michael/Diels-Alder/oxa-Michael Dimerization of para-Quinols.

A bio-inspired, pyrrolidine-mediated, dimerization of para-quinols has been developed. It represents one of the most complex, yet general, dimerization reactions ever disclosed, selectively forming four new bonds, four new rings, and eight new contiguous stereogenic centres. The para-quinol starting materials are easily handled, bench-stable compounds, accessed in just one step from aromatic feedstocks. The reaction can be scaled up to give grams of polycyclic material, primed for further elaboration.

Application of the aza-Diels-Alder reaction in the synthesis of natural products.

The Diels-Alder reaction that involves a nitrogen atom in the diene or dienophile is termed the aza-Diels-Alder reaction. As well as the powerful all-carbon Diels-Alder reaction, the aza-Diels-Alder reaction has also played an important role in the total synthesis of natural products. Herein, we review various natural products using an aza-Diels-Alder reaction as a key step to their total synthesis, and divide the syntheses into inter- and intra-molecular aza-Diels-Alder reactions and a retro-aza-Diels-Alder reaction. Inter- and intra-molecular aza-Diels-Alder reactions involve an imine as an electron deficient dienophile and an imine as an electron deficient azadiene. The significance of the aza-Diels-Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.

Scavenging and recombination kinetics in radiation chemistry.

This work describes stochastic models developed to study the competition between radical scavenging and recombination for simple model systems typical of radiation chemistry, where the reactive particles are tightly clustered and reactions are assumed fully diffusion limited. Three models are developed: a Monte Carlo random flights model with a periodic boundary condition for scavengers, Monte Carlo simulations in which the scavenging rate is calculated from the Smoluchowski theory for diffusion-limited reactions and a modification of the independent reaction times method where the scavengers close to the spur are explicitly included and the scavengers further away are treated as a continuum. The results indicate that the Smoluchowski theory makes a systematic overestimate of the scavenging rate when such competition is present. A correction for the Smoluchowski rate constant is suggested, an analytical justification is presented and it is tested against the simulations, and shown to be a substantial improvement.

Markers of physiological stress during exercise under conditions of normoxia, normobaric hypoxia, hypobaric hypoxia, and genuine high altitude.

PURPOSE: To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH), and normobaric normoxia (NN). METHOD: Markers of sympathoadrenal and adrenocortical function [plasma normetanephrine (PNORMET), metanephrine (PMET), cortisol], myocardial injury [highly sensitive cardiac troponin T (hscTnT)], and function [N-terminal brain natriuretic peptide (NT-proBNP)] were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 h [15-min warm-up, 105 min at 55% Wmax (maximal workload)] with venous blood samples taken prior (T0), immediately following (T120) and 2-h post-exercise (T240). RESULTS: Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET. CONCLUSION: Biochemical markers that reflect sympathoadrenal, adrenocortical, and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia, while NH and HH appear to induce broadly similar responses to GHA and may, therefore, be reasonable surrogates.

Clinical outcomes and costs for people with complex psychosis; a naturalistic prospective cohort study of mental health rehabilitation service users in England.

BACKGROUND: Mental health rehabilitation services in England focus on people with complex psychosis. This group tend to have lengthy hospital admissions due to the severity of their problems and, despite representing only 10-20 % of all those with psychosis, they absorb 25-50 % of the total mental health budget. Few studies have investigated the effectiveness of these services and there is little evidence available to guide clinicians working in this area. As part of a programme of research into inpatient mental health rehabilitation services, we carried out a prospective study to investigate longitudinal outcomes and costs for patients of these services and the predictors of better outcome. METHOD: Inpatient mental health rehabilitation services across England that scored above average (median) on a standardised quality assessment tool used in a previous national survey were eligible for the study. Unit quality was reassessed and costs of care and patient characteristics rated using standardised tools at recruitment. Multivariable regression modelling was used to investigate the relationship between service quality, patient characteristics and the following clinical outcomes at 12 month follow-up: social function; length of admission in the rehabiliation unit; successful community discharge (without readmission or community placement breakdown) and costs of care. RESULTS: Across England, 50 units participated and 329 patients were followed over 12 months (94 % of those recruited). Service quality was not associated with patients' social function or length of admission (median 16 months) at 12 months but most patients were successfully discharged (56 %) or ready for discharge (14 %), with associated reductions in the costs of care. Factors associated with successful discharge were the recovery orientation of the service (OR 1.04, 95 % CI 1.00-1.08), and patients' activity (OR 1.03, 95 % CI 1.01-1.05) and social skills (OR 1.13, 95 % CI 1.04-1.24) at recruitment. CONCLUSION: Inpatient mental health rehabilitation services in England are able to successfully discharge over half their patients within 18 months, reducing the costs of care for this complex group. Provision of recovery orientated practice that promotes patients' social skills and activities may further enhance the effectiveness of these services.

Direct Cross-Couplings of Propargylic Diols.

[Pd(PPh3 )4 ] catalyzes a Suzuki-Miyaura-like twofold cross-coupling sequence between underivatized propargylic diols and either aryl or alkenyl boronic acids to furnish highly substituted 1,3-dienes. Thus, 2,3-diaryl-1,3-butadienes and their dialkenic congeners ([4]dendralenes) are delivered in a (pseudo)halogen-free, single-step synthesis which supersedes existing methods. Allenols are also readily formed. Treatment of these single- and twofold cross-coupled products with acid leads to remarkably short syntheses of highly-substituted benzofulvenes and aryl indenes, respectively.

Barriers to the sustainability of an intervention designed to improve patient engagement within NHS mental health rehabilitation units: a qualitative study nested within a randomised controlled trial.

BACKGROUND: We undertook a cluster randomised controlled trial to assess the effectiveness of a staff training intervention to improve patient engagement in activities in inpatient mental health rehabilitation units. Concurrently, we undertook a qualitative study to investigate the experiences of staff within the intervention units and the contextual issues that may have influenced the effectiveness of the intervention. METHOD: We conducted focus groups with staff working in the inpatient units that received the intervention, sampled using a maximum variation strategy. RESULTS: The intervention was accepted by staff. However, the skills gained, and changes to the unit's processes and structures that were agreed with the intervention team were not sustained after they left. The main reasons for this were a) external factors (economic recession, resource limitations); b) organisation level factors (lack of senior staff support; competing priorities); c) limitations of the intervention itself (length of intensive training period; reinforcement of skills). CONCLUSION: This study illustrates some of the inter-related factors which operate at different levels within and outside of NHS organisations that may impact on the success of complex interventions. These factors need to be considered when designing interventions to ensure adequate buy-in from senior staff. TRIAL REGISTRATION: Current Controlled Trials ISRCTN25898179 (Registered 23 April 2010).

Individual budgets for people with incontinence: results from a 'shopping' experiment within the British National Health Service.

BACKGROUND AND CONTEXT: Most people with urinary incontinence are given limited choice when provided with absorbent products through the British National Health Service (NHS), even though the available range is large. OBJECTIVE: To investigate users' preferences for four disposable designs (inserts, all-in-ones, belted/T-shaped and pull-ups) and towelling washable/reusable products, day and night. DESIGN: Shopping experiment. SETTING AND PARTICIPANTS: Community-dwelling women and men in England with moderate-to-heavy urinary incontinence recruited to a larger trial. INTERVENTION: Participants tested each design and selected products they would prefer with a range of different budgets. MAIN OUTCOME MEASURES: Design preferences (rankings); 'purchasing' decisions from designated budgets. Results Eighty-five participants (49 men) tested products, 75 completed the shopping experiment. Inserts, most frequently supplied by the NHS, were ranked second to pull-ups by women and lowest by men. When faced with budget constraints, up to 40% of participants opted to 'mix-and-match' designs. Over 15 different combinations of products were selected by participants in the shopping experiment. Most (91%) stated a willingness to 'top-up' assigned budgets from income to secure preferred designs. DISCUSSION: Participants displayed diverse preferences. Enabling user choice of absorbent product design through individual budgets could improve satisfaction of consumers and efficiency of allocation of limited NHS resources. CONCLUSION: Recent policy for the NHS seeks to provide consumers with more control in their care. Extension of the concept of individual budgets to continence supplies could be feasible and beneficial for patients and provide better value-for-money within the NHS. Further research is warranted.

Barriers to Eye Care for Adults in the United States and Solutions for It: A Literature Review.

Vision loss and blindness is a significant public health concern that has had a profound impact on various communities in the United States. Both anticipated and unforeseen barriers have been linked to the rising rates of vision loss and blindness in the country. Extensive research has identified numerous barriers that put many Americans at a disadvantage when trying to seek high-quality eye care services. Not only do the barriers to eye care services create problems for eye health, but also create a poor quality of life. Therefore, understanding and identifying barriers to eye healthcare services is incredibly important. In addition to understanding and identifying barriers, it is also important to identify solutions to the problems created by these barriers. A systematic review of articles characterizing the barriers to eye care was completed which resulted in the identification of the major barriers that affect Americans. The review of previous research was also used to identify available solutions for problems associated with the barriers to eye care services. The major barriers identified were cost, insurance, transport and accessibility, eye health care literacy, and communication. Because of the identification of the major barriers, solutions were also identified. Health education and increased vision screenings were found to be the most used forms of solutions by healthcare professionals promoting good eye health. Telemedicine has also been cited as a possible solution to the growing problem of visual impairment and blindness within the American population.

Plate fixation optimization for distal femoral fractures with segmental bone loss: Defining the preferred screw distribution using finite element analysis.

OBJECTIVES: Distal femur fractures can exhibit extensive comminution, and open fractures may result in bone loss. These injuries are under high mechanical demands when stabilized with a lateral locked plate (LLP), and are at risk of non-union or implant failure. This study investigates the optimal LLP screw configuration for distal femur fractures with a large metadiaphyseal gap of 5 cm. METHODS: A finite element (FE) model, validated against experimentally measured strains and displacement, evaluated pull-out forces and stress concentration on typical implants under clinical conditions corresponding with the 10 % point during the stance phase of the gait cycle. RESULTS: Maximum stress was up to 83 % less when the ratio (Cp) between the proximal screw-distribution-length and the distance of the first screw to the fracture was less than 0.2; maximum pull-out force was 99 % less when this ratio was higher than 0.4. CONCLUSIONS: Screw configuration based on either normal or osteopenic bone quality plays an important role in determining the risk of construct failure for a major (50 mm) distal femoral metadiaphyseal segmental defect. This study provides valuable information when planning definitive fixation for distal femur fractures with extensive comminution or segmental bone defects, to mitigate the risk of implant failure and subsequent nonunion.

Service quality and clinical outcomes: an example from mental health rehabilitation services in England.

BACKGROUND: Current health policy assumes better quality services lead to better outcomes. AIMS: To investigate the relationship between quality of mental health rehabilitation services in England, local deprivation, service user characteristics and clinical outcomes. METHOD: Standardised tools were used to assess the quality of mental health rehabilitation units and service users' autonomy, quality of life, experiences of care and ratings of the therapeutic milieu. Multiple level modelling investigated relationships between service quality, service user characteristics and outcomes. RESULTS: A total of 52/60 (87%) National Health Service trusts participated, comprising 133 units and 739 service users. All aspects of service quality were positively associated with service users' autonomy, experiences of care and therapeutic milieu, but there was no association with quality of life. CONCLUSIONS: Quality of care is linked to better clinical outcomes in people with complex and longer-term mental health problems. Thus, investing in quality is likely to show real clinical gains.