SLC19A1 Genetic Variation Leads to Altered Thiamine Diphosphate Transport: Implications for the Risk of Developing Wernicke-Korsakoff's Syndrome.

AIMS: Wernicke-Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells. METHODS: Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls. RESULTS: Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case-control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10-11). CONCLUSION: This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells.

CHARMM-GUI Supports Hydrogen Mass Repartitioning and Different Protonation States of Phosphates in Lipopolysaccharides.

Hydrogen mass repartitioning (HMR) that permits time steps of all-atom molecular dynamics simulation up to 4 fs by increasing the mass of hydrogen atoms has been used in protein and phospholipid bilayers simulations to improve conformational sampling. Molecular simulation input generation via CHARMM-GUI now supports HMR for diverse simulation programs. In addition, considering ambiguous pH at the bacterial outer membrane surface, different protonation states, either -2e or -1e, of phosphate groups in lipopolysaccharides (LPS) are also supported in CHARMM-GUI LPS Modeler. To examine the robustness of HMR and the influence of protonation states of phosphate groups on LPS bilayer properties, eight different LPS-type all-atom systems with two phosphate protonation states are modeled and simulated utilizing both OpenMM 2-fs (standard) and 4-fs (HMR) schemes. Consistency in the conformational space sampled by standard and HMR simulations shows the reliability of HMR even in LPS, one of the most complex biomolecules. For systems with different protonation states, similar conformations are sampled with a PO41- or PO42- group, but different phosphate protonation states make slight impacts on lipid packing and conformational properties of LPS acyl chains. Systems with PO41- have a slightly smaller area per lipid and thus slightly more ordered lipid A acyl chains compared to those with PO42-, due to more electrostatic repulsion between PO42- even with neutralizing Ca2+ ions. HMR and different protonation states of phosphates of LPS available in CHARMM-GUI are expected to be useful for further investigations of biological systems of diverse origin.

Reduced Radial Displacement of the Gastrocnemius Medialis Muscle After Electrically Elicited Fatigue.

CONTEXT: Assessments of skeletal-muscle functional capacity often necessitate maximal contractile effort, which exacerbates muscle fatigue or injury. Tensiomyography (TMG) has been investigated as a means to assess muscle contractile function after fatigue; however, observations have not been contextualized by concurrent physiological measures. OBJECTIVE: To measure peripheral-fatigue-induced alterations in mechanical and contractile properties of the plantar-flexor muscles through noninvasive TMG concurrently with maximal voluntary contraction (MVC) and passive muscle tension (PMT) to validate TMG as a gauge of peripheral fatigue. DESIGN: Pre- and posttest intervention with control. SETTING: University laboratory. PARTICIPANTS: 21 healthy male volunteers. INTERVENTIONS: Subjects' plantar flexors were tested for TMG parameters, along with MVC and PMT, before and after either a 5-min rest period (control) or a 5-min electrical-stimulation intervention (fatigue). MAIN OUTCOME MEASURES: Temporal (contraction velocity) and spatial (radial displacement) contractile parameters of the gastrocnemius medialis were recorded through TMG. MVC was measured as an indicator of muscle fatigue, and PMT was measured to assess muscle stiffness. RESULTS: Radial displacement demonstrated a fatigue-associated reduction (3.3 ± 1.2 vs 4.0 ± 1.4 mm, P = .031), while contraction velocity remained unaltered. In addition, MVC significantly declined by 122.6 ± 104 N (P < .001) after stimulation (fatigue). PMT was significantly increased after fatigue (139.8 ± 54.3 vs 111.3 ± 44.6 N, P = .007). CONCLUSION: TMG successfully detected fatigue, evident from reduced MVC, by displaying impaired muscle displacement accompanied by elevated PMT. TMG could be useful in establishing skeletal-muscle fatigue status without exacerbating the functional decrement of the muscle.

A prospective observational study of abdominal injury management in contemporary military operations: damage control laparotomy is associated with high survivability and low rates of fecal diversion.

OBJECTIVE: This study describes the cause, management, and outcomes of abdominal injury in a mature deployed military trauma system, with particular focus on damage control, hollow visceral injury (HVI), and stoma utilization. BACKGROUND: Damage control laparotomy (DCL) is established in military and civilian practice. However, optimal management of HVI during military DCL remains controversial. METHODS: We studied abdominal trauma managed over 5 months at the Joint Force Combat Support Hospital, Camp Bastion, Afghanistan (Role 3). Data included demographics, wounding mechanism, injuries sustained, prehospital times, location of first laparotomy (Role 3 or forward), use of DCL or definitive laparotomy, subsequent surgical details, resource utilization, complications, and mortality. RESULTS: Ninety-four of 636 trauma patients (15%) underwent laparotomy. Military injury mechanisms dominated [44 gunshot wounds (47%), 44 blast (47%), and 6 blunt trauma (6%)]. Seventy-two of 94 patients (77%) underwent DCL. Four patients were palliated. Seventy of 94 (74%) sustained HVI; 44 of 70 (63%) had colonic injury. Repair or resection with anastomosis was performed in 59 of 67 therapeutically managed HVI patients (88%). Six patients were managed with fecal diversion, and 6 patients were evacuated with discontinuous bowel. Anastomotic leaks occurred in 4 of 56 HVI patients (7%) with known outcomes. Median New Injury Severity Score for DCL patients was 29 (interquartile range: 18-41) versus 19.5 (interquartile range: 12-34) for patients undergoing definitive laparotomy (P = 0.016). Overall mortality was 15 of 94 (16%). CONCLUSIONS: Damage control is now used routinely for battlefield abdominal trauma. In a well-practiced Combat Support Hospital, this strategy is associated with low mortality and infrequent fecal diversion.

Scanning and War: Utility of FAST and CT in the Assessment of Battlefield Abdominal Trauma.

OBJECTIVE: To determine utilization and accuracy of focused assessment with sonography for trauma (FAST) and computed tomography (CT) in a mature military trauma system to inform service provision for future conflicts. BACKGROUND: FAST and CT scans undertaken by attending radiologists contribute to surgical decision making for battlefield casualties at the Joint Force, Role 3 Medical Treatment Facility at Camp Bastion (R3), Afghanistan. METHODS: Registry data for abdominally injured casualties treated at R3 from July to November 2012 were matched to radiological and surgical records to determine diagnostic accuracy for FAST and CT and their influence on casualty management. RESULTS: A total of 468 casualties met inclusion criteria, of whom 85.0% underwent FAST and 86.1% abdominal CT; 159 (34.0%) had abdominal injuries. For detection of intra-abdominal injury, FAST sensitivity (Sn) was 0.56, specificity (Sp) 0.98, positive predictive value (PPV) 0.87, negative predictive value (NPV) 0.90, and accuracy (Acc) 0.89. For CT, Sn was 0.99, Sp 0.99, PPV 0.96, NPV 1.00, and Acc 0.99. Forty-six solid organ injuries were identified in 38 patients by CT; 17 were managed nonoperatively. A further 61 patients avoided laparotomy after CT confirmed extra-abdominal wounds only. The negative laparotomy rate was 3.9%. CONCLUSIONS: FAST and CT contribute to triage, guide surgical management, and reduce nontherapeutic laparotomy. When imaging is available, these data challenge current doctrine about inadvisability of nonoperative management of abdominal injury after combat trauma.

Genetic variants in or near ADH1B and ADH1C affect susceptibility to alcohol dependence in a British and Irish population.

Certain single nucleotide polymorphisms (SNPs) in genes encoding alcohol dehydrogenase (ADH) enzymes confer a significant protective effect against alcohol dependence syndrome (ADS) in East Asian populations. Recently, attention has focused on the role of these SNPs in determining ADS risk in European populations. To further elucidate these associations, SNPs of interest in ADH1B, ADH1C and the ADH1B/1C intergenic region were genotyped in a British and Irish population (ADS cases n = 1076: controls n = 1027) to assess their relative contribution to ADS risk. A highly significant, protective association was observed between the minor allele of rs1229984 in ADH1B and ADS risk [allelic P = 8.4 × 10(-6) , odds ratio (OR) = 0.26, 95 percent confidence interval, 0.14, 0.49]. Significant associations were also observed between ADS risk and the ADH1B/1C intergenic variant, rs1789891 [allelic P = 7.2 × 10(-5) , OR = 1.4 (1.2, 1.6)] and three non-synonymous SNPs rs698, rs1693482 and rs283413 in ADH1C. However, these associations were not completely independent; thus, while the ADH1B rs1229984 minor allele association was independent of those of the intergenic variant rs1789891 and the three ADH1C variants, the three ADH1C variants were not individually independent. In conclusion, the rare ADH1B rs1229984 mutation provides significant protection against ADS in this British and Irish population; other variants in the ADH gene cluster also alter ADS risk, although the strong linkage disequilibrium between SNPs at this location precluded clear identification of the variant(s) driving the associations.

Molecular Crowding Alters the Interactions of Polymyxin Lipopeptides within the Periplasm of E. coli: Insights from Molecular Dynamics.

The cell envelope of Gram-negative bacteria is a crowded tripartite architecture that separates the cell interior from the external environment. Two membranes encapsulate the aqueous periplasm, which contains the cell wall. Little is known about the mechanisms via which antimicrobial peptides move through the periplasm from the outer membrane to their site of action, the inner membrane. We utilize all-atom molecular dynamics to study two antimicrobial peptides, polymyxins B1 and E, within models of the E. coli periplasm crowded to different extents. In a simple chemical environment, both PMB1 and PME bind irreversibly to the cell wall. The presence of specific macromolecules leads to competition with the polymyxins for cell wall interaction sites, resulting in polymyxin dissociation from the cell wall. Chemical complexity also impacts interactions between polymyxins and Braun's lipoprotein; thus, the interaction modes of lipoprotein antibiotics within the periplasm are dependent upon the nature of the other species present.

Building lean improvement sckills at scale: an evaluation of a massive open online course in the English NHS.

BACKGROUND: Internationally, healthcare systems face challenges from population demographics and rising care costs. Systematic methods of quality improvement (QI) are considered key to delivering needed transformation and change. Large-scale training in QI skills is required.Massive open online courses (MOOCs) are an inexpensive strategy for QI training across large regions and countries. The Lean Fundamentals MOOC was developed in the English NHS to train health and care staff in Lean QI methods. It supported participants to learn and apply process improvement skills through a free-to-access, practical, learning-in-action approach. METHODS: Lean Fundamentals' cost-effectiveness and its impact on participants' knowledge and confidence to apply Lean to improve processes were assessed. Using the Kirkpatrick framework, participant reaction, knowledge and confidence change, results and overall return-on-investment (ROI) were evaluated. Quantitative data were collected via pre and postcourse surveys to analyse participants' knowledge and confidence change using the Wilcoxon signed rank test. Qualitative learning platform and postcourse survey data demonstrated participants' results from application. RESULTS: Over 18 months, Lean Fundamentals attracted 6617 enrolments and supported 3462 active participants. 97.6% (n=829) of participants completing the postcourse survey indicated Lean Fundamentals met their expectations and 97.2% (n=823) indicated they would recommend it. Self-reported changes in knowledge and confidence to apply Lean showed significant differences (p<0.001). Learning was applied to operational healthcare priorities (such as post-COVID recovery of services) and participants shared 511 project improvement reports. CONCLUSION: Lean Fundamentals helped large numbers of participants to develop Lean process improvement skills-avoiding costs associated with commercial Lean training in the range £1.7 m to £3.4 m and generating ROI of between £11 and £23 per every pound spent on delivery. This demonstrates that massive online is an effective and efficient method for building improvement knowledge and skills at scale.

Alcohol minimum unit pricing and people experiencing homelessness: A qualitative study of stakeholders' perspectives and experiences.

INTRODUCTION: Minimum unit pricing (MUP) may reduce harmful drinking in the general population, but there is little evidence regarding its impact on marginalised groups. Our study is the first to explore the perceptions of MUP among stakeholders working with people experiencing homelessness following its introduction in Scotland in May 2018. METHODS: Qualitative semi-structured interviews were conducted with 41 professional stakeholders from statutory and third sector organisations across Scotland. We explored their views on MUP and its impact on people experiencing homelessness, service provision and implications for policy. Data were analysed using thematic analysis. RESULTS: Participants suggested that the introduction of MUP in Scotland had negligible if any discernible impact on people experiencing homelessness and services that support them. Most service providers felt insufficiently informed about MUP prior to its implementation. Participants reported that where consequences for these populations were evident, they were primarily anticipated although some groups were negatively affected. People experiencing homelessness have complex needs in addition to alcohol addiction, and changes in the way services work need to be considered in future MUP-related discussions. DISCUSSION AND CONCLUSIONS: This study suggests that despite initial concerns about potential unintended consequences of MUP, many of these did not materialise to the levels anticipated. As a population-level health policy, MUP is likely to have little beneficial impact on people experiencing homelessness without the provision of support to address their alcohol use and complex needs. The additional needs of certain groups (e.g., people with no recourse to public funds) need to be considered.

The impact of alcohol minimum unit pricing on people with experience of homelessness: Qualitative study.

BACKGROUND: Alcohol Minimum Unit Pricing (MUP) was introduced in Scotland in May 2018. Existing evidence suggests MUP can reduce alcohol consumption in the general population, but there is little research about its impact on vulnerable groups. This qualitative study explored experiences of MUP among people with experience of homelessness. METHODS: We conducted qualitative semi-structured interviews with a purposive sample of 46 people with current or recent experience of homelessness who were current drinkers when MUP was introduced. Participants (30 men and 16 women) were aged 21 to 73 years. Interviews focused on views and experiences of MUP. Data were analysed using thematic analysis. RESULTS: People with experience of homelessness were aware of MUP but it was accorded low priority in their hierarchy of concerns. Reported impacts varied. Some participants reduced their drinking, or moved away from drinking strong white cider, in line with policy intentions. Others were unaffected because the cost of their preferred drink (usually wine, vodka or beer) did not change substantially. A minority reported increased involvement in begging. Wider personal, relational and social factors also played an important role in responses to MUP. CONCLUSION: This is the first qualitative study to provide a detailed exploration of the impact of MUP among people with experience of homelessness. Our findings suggest that MUP worked as intended for some people with experience of homelessness, while a minority reported negative consequences. Our findings are of international significance to policymakers, emphasising the need to consider the impact of population level health policies on marginalised groups and the wider contextual factors that affect responses to policies within these groups. It is important to invest further in secure housing and appropriate support services and to implement and evaluate harm reduction initiatives such as managed alcohol programmes.

Computational microbiology of bacteria: Advancements in molecular dynamics simulations.

Microbiology is traditionally considered within the context of wet laboratory methodologies. Computational techniques have a great potential to contribute to microbiology. Here, we describe our loose definition of "computational microbiology" and provide a short survey focused on molecular dynamics simulations of bacterial systems that fall within this definition. It is our contention that increased compositional complexity and realistic levels of molecular crowding within simulated systems are key for bridging the divide between experimental and computational microbiology.

Genome-wide association study of antisocial personality disorder diagnostic criteria provides evidence for shared risk factors across disorders.

INTRODUCTION: While progress has been made in determining the genetic basis of antisocial behaviour, little progress has been made for antisocial personality disorder (ASPD), a condition that often co-occurs with other psychiatric conditions including substance use disorders, attention deficit hyperactivity disorder (ADHD), and anxiety disorders. This study aims to improve the understanding of the genetic risk for ASPD and its relationship with other disorders and traits. METHODS: We conducted a genome-wide association study (GWAS) of the number of ASPD diagnostic criteria data from 3217 alcohol-dependent participants recruited in the UK (UCL, N = 644) and the USA (Yale-Penn, N = 2573). RESULTS: We identified rs9806493, a chromosome 15 variant, that showed a genome-wide significant association ( Z -score = -5.501, P = 3.77 × 10 -8 ) with ASPD criteria. rs9806493 is an eQTL for SLCO3A1 (Solute Carrier Organic Anion Transporter Family Member 3A1), a ubiquitously expressed gene with strong expression in brain regions that include the anterior cingulate and frontal cortices. Polygenic risk score analysis identified positive correlations between ASPD and smoking, ADHD, depression traits, and posttraumatic stress disorder. Negative correlations were observed between ASPD PRS and alcohol intake frequency, reproductive traits, and level of educational attainment. CONCLUSION: This study provides evidence for an association between ASPD risk and SLCO3A1 and provides insight into the genetic architecture and pleiotropic associations of ASPD.

Recovering staff, recovering services: massive-online support for recovering a paediatric service using Lean and compassionate communication.

The COVID-19 pandemic has infected tens of millions worldwide. Healthcare systems have been stretched caring for the most seriously ill and healthcare workers have struggled to maintain non-COVID services leading to backlogs.Strategies proposed to support the recovery of backlogs include additional administration support; waiting list data validation; enhanced patient communication; and use of systematic improvement methods to make rapid incremental improvements.As part of COVID-19 recovery, a hospital trust in northern England used the Lean systematic improvement approach to recover the waiting list of a paediatric service to pre-COVID levels. The intervention strategy used a massive-open-online-course (Lean Fundamentals) to support the improvement project lead to follow a structured improvement routine to apply Lean improvement techniques.By acknowledging that staff were overburdened by the requirements of COVID-19 and that patients were stuck in a system of disconnected processes, administrative activities were redesigned around an ethos of compassionate communication that put patients first.Over a period of 8 weeks, the project reduced the waiting list from 1109 to 212. Waiting times were reduced from a maximum of 36 months to a 70-day average.Lean is often described in terms of increasing process efficiency and productivity. It is not often associated with staff benefits. However, when seen in the context of unburdening staff to deliver patient care, Lean has potential to support the recovery of both staff and services. Lean Fundamentals, with its accessible massive-online design, may provide a means of supporting such improvement at scale.

Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS: Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS: From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION: The trial did not show that prehospital PRBC-LyoPlas resuscitation was superior to 0·9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation.

Capability building for large-scale transformational change: learning from an evaluation of a national programme.

BACKGROUND: The Long Term Plan presents an ambitious vision for England's National Health Service which will require a sustained programme of transformational change. The Virtual Academy of Large-Scale Change (VALSC) was developed to build capability in health and care system teams involved in transformation or redesign programmes. METHODS: To evaluate the VALSC, quantitative and qualitative data were collected and reviewed against the Kirkpatrick model. Quantitative data were collected via end-of-session surveys to assess individual knowledge before and after participating in capability-building interventions. Qualitative data were also collected and included post-intervention surveys and interviews. Interviews were transcribed and analysed using an inductive approach to identify themes that were subsequently assessed against the Kirkpatrick model. RESULTS: Results suggest that the VALSC programme has helped build capability for large-scale change in terms of learning, behaviour change and impact. Participants' ipsative self-assessment of knowledge demonstrated a significant change (p<0.001) and qualitative data suggested three broad themes in which the VALSC made an impact. First, participants were empowered with transformation and change skills which they applied to local health and care challenges. Second, VALSC helped strengthen connections within and between transformational change teams. Third, VALSC helped transformational change teams to engage more effectively with their stakeholders. CONCLUSIONS: The VALSC developed knowledge, skills, behavioural change and application impact that built capability in individuals and teams. Therefore, continuing to develop capability-building offers that empower and build agency in front-line staff working on service transformation and equip them with approaches, methods and tools to increase their chances of success, is recommended.

Mass production methods for mass vaccination: improving flow and operational performance in a COVID-19 mass vaccination centre using Lean.

The COVID-19 pandemic has infected tens of millions of people worldwide causing many deaths. Healthcare systems have been stretched caring for the most seriously ill and lockdown measures to interrupt COVID-19 transmission have had adverse economic and societal impacts. Large-scale population vaccination is seen as the solution.In the UK, a network of sites to deploy vaccines comprised National Health Service hospitals, primary care and new mass vaccination centres. Due to the pace at which mass vaccination centres were established and the scale of vaccine deployment, some sites experienced problems with queues and waiting times. To address this, one site used the Lean systematic improvement approach to make rapid operational improvements to reduce process times and improve flow.The case example identifies obstacles to flow experienced by a mass vaccination centre and how they were addressed using Lean concepts and techniques. Process cycle times were used as a proxy metric for efficiency and flow. Based on daily demand volume and open hours, takt time was calculated to give a process completion rate to achieve flow through the vaccination centre.The mass vaccination centre achieved its aim of reducing process times and improving flow. Administrative and clinical cycle times were reduced sufficiently to increase throughput and the number of queues and queueing time were reduced improving client experience.The design and operational management of vaccination centre processes contribute to client experience, efficiency and throughput. Lean provides a systematic approach that can improve operational processes and facilitate client flow through mass vaccination centres.

Operations management on the front line of COVID-19 vaccination: building capability at scale via technology-enhanced learning.

The globe is gripped by the COVID-19 pandemic. Mass population vaccination is seen as the solution. As vaccines become available, governments aim to deploy them as rapidly as possible. It is important, therefore, that the efficiency of vaccination processes is optimal.Operations management is concerned with improving processes and comprises systematic approaches such as Lean. Lean focuses explicitly on process efficiency through the elimination of non-value adding steps to optimise processes for those who use and depend on them.Technology-enhanced learning can be a strategy to build improvement capability at scale. A massive online programme to build capability in Lean has been developed by the regulator of England's National Health Service. Beta testing of this programme has been used by some test sites to refine their COVID-19 vaccination processes. The paper presents a case example of massive online learning supporting the use of Lean in the day-to-day operations management of COVID-19 vaccine processes.The case example illustrates the challenges that vaccination processes may present and the need for responsive and effective operations management. Building capability to respond rapidly and systematically in dynamic situations to optimise flow, safety and patient experience may be beneficial.Given the national imperative to achieve mass vaccination as rapidly as possible, systematic improvement methods such as Lean may have a contribution to make. Massive online programmes, such as that described here, may help with this effort by achieving timely knowledge transfer at large scale.

Driving quality improvement with a massive open online course (MOOC).

BACKGROUND: Quality improvement (QI) is a priority for national regulatory bodies in health and care in the UK. However, many health and care staff do not know where to go for support in gaining the required skills and knowledge in QI. This paper reviews Improvement Fundamentals, a massive open online course (MOOC), designed to address this gap, run by an improvement team in the national regulatory body. METHODS: In 2015, National Health Service (NHS) Improving Quality (subsequently the sustainable improvement team in NHS England) established Improvement Fundamentals: a programme of online, self-directed courses in QI for those involved in heath or social care. The programme ran in two cycles: twice in 2015, followed by a re-launch in 2018 (this programme also ran into 2019). A mixed-methods evaluation was carried out of the 2015 programme involving surveys, interviews and social listening. The 2018-2019 programme was evaluated using post-course surveys of participants and activity data from the platform. OUTCOMES: Since the start of the 2015 programme, 604 improvement projects have been developed, run and submitted for formal assessment, with some demonstrating clear improvements in services. Themes from participant feedback on both programmes have included improved understanding of QI tools and methods; greater energy for QI; a greater sense of community and connectedness in participants' work and increased confidence in using QI tools and techniques. DISCUSSION: Both programmes delivered benefits for participants, and the team's investment in improvement skills on these programmes has helped to increase capability for future change endeavours. The collaborative nature of the programmes has been key to their successes. CONCLUSION: Improvement Fundamentals demonstrates that MOOCs can be instrumental in driving forward improvements in health and care. The programmes may have utility as a model for future MOOCs, both in QI and other topics, to help drive further improvements in health and care.

The hitchhiker's guide to the periplasm: Unexpected molecular interactions of polymyxin B1 in E. coli.

The periplasm of Gram-negative bacteria is a complex, highly crowded molecular environment. Little is known about how antibiotics move across the periplasm and the interactions they experience. Here, atomistic molecular dynamics simulations are used to study the antibiotic polymyxin B1 within models of the periplasm, which are crowded to different extents. We show that PMB1 is likely to be able to "hitchhike" within the periplasm by binding to lipoprotein carriers-a previously unreported passive transport route. The simulations reveal that PMB1 forms both transient and long-lived interactions with proteins, osmolytes, lipids of the outer membrane, and the cell wall, and is rarely uncomplexed when in the periplasm. Furthermore, it can interfere in the conformational dynamics of native proteins. These are important considerations for interpreting its mechanism of action and are likely to also hold for other antibiotics that rely on diffusion to cross the periplasm.

The influence of regression models on genome-wide association studies of alcohol dependence: a comparison of binary and quantitative analyses.

INTRODUCTION: Genome-wide association studies (GWAS) of alcohol dependence syndrome (ADS) offer a platform to detect genetic risk loci. However, the majority of the ADS GWAS undertaken, to date, have utilized a case-control design and have failed to identify consistently replicable loci with the exception of protective variants within the alcohol metabolizing genes, notably ADH1B. The ADS phenotype shows considerable variability which means that the use of quantitative variables as a proxy for the severity of ADS has the potential to facilitate identification of risk loci by increasing statistical power. The current study aims to examine the influences of using binary and adjusted quantitative measures of ADS on GWAS outcomes and on calculated polygenic risk scores (PRS). METHODS: A GWAS was performed in 1251 healthy controls with no history of excess alcohol use and 739 patients with ADS classified using binary DMS-IV criteria. Two additional GWAS were undertaken using a quantitative score based on DSM-IV criteria, which were applied assuming both normal and non-normal distributions of the phenotypic variables. PRS analyses were performed utilizing the data from the binary and the quantitative trait analyses. RESULTS: No associations were identified at genome-wide significance in any of the individual GWAS; results were comparable in all three. The top associated single nucleotide polymorphism was located on the alcohol dehydrogenase gene cluster on chromosome 4, consistent with previous ADS GWAS. The quantitative trait analysis adjusted for the distribution of the criterion score and the associated PRS had the smallest standard errors and thus the greatest precision. CONCLUSION: Further exploitation of the use of qualitative trait analysis in GWAS in ADS is warranted.