Structural dynamics around a hydrogen bond: Investigating the effect of hydrogen bond strengths on the excited state dynamics of carboxylic acid dimers.

The photochemical dynamics of the acetic acid and trifluoro-acetic acid dimers in hexane are studied using time-resolved infrared absorption spectroscopy and ab initio electronic structure calculations. The different hydrogen bond strengths of the two systems lead to changes in the character of the accessed excited states and in the timescales of the initial structural rearrangement that define the early time dynamics following UV excitation. The much stronger hydrogen bonding in the acetic acid dimer stabilizes the system against dissociation. Ground state recovery is mediated by a structural buckling around the hydrogen bond itself with no evidence for excited state proton transfer processes that are usually considered to drive ultrafast relaxation processes in hydrogen bonded systems. The buckling of the ring leads to relaxation through two conical intersections and the eventual reformation of the electronic and vibrational ground states on a few picosecond timescale. In trifluoro-acetic acid, the weaker hydrogen bonding interaction means that the dimer dissociates under similar irradiation conditions. The surrounding solvent cage restricts the full separation of the monomer components, meaning that the dimer is reformed and returns to the ground state structure via a similar buckled structure but over a much longer, ∼100 ps, timescale.

Nuclear Magnetic Resonance Chemical Shift as a Probe for Single-Molecule Charge Transport.

Existing modelling tools, developed to aid the design of efficient molecular wires and to better understand their charge-transport behaviour and mechanism, have limitations in accuracy and computational cost. Further research is required to develop faster and more precise methods that can yield information on how charge transport properties are impacted by changes in the chemical structure of a molecular wire. In this study, we report a clear semilogarithmic correlation between charge transport efficiency and nuclear magnetic resonance chemical shifts in multiple series of molecular wires, also accounting for the presence of chemical substituents. The NMR data was used to inform a simple tight-binding model that accurately captures the experimental single-molecule conductance values, especially useful in this case as more sophisticated density functional theory calculations fail due to inherent limitations. Our study demonstrates the potential of NMR spectroscopy as a valuable tool for characterising, rationalising, and gaining additional insights on the charge transport properties of single-molecule junctions.

"Turning up the heat": role of neurotrophic batokines in the postnatal maturation and remodeling of brown adipose tissue in deer mice.

Activation of brown adipose tissue (BAT) thermogenesis impacts energy balance and must be tightly regulated. Several neurotrophic factors, expressed in BAT of adult laboratory rodents, have been implicated in remodeling the sympathetic neural network to enhance thermogenesis [e.g., nerve growth factor (NGF), neuregulin-4 (NRG4), and S100b]. Here, we compare, to our knowledge, for the first time, the relative roles of three neurotrophic "batokines" in establishing/remodeling innervation during postnatal development and adult cold stress. We used laboratory-reared Peromyscus maniculatus, which rely heavily on BAT-based thermogenesis for survival in the wild, beginning between postnatal days (P) 8 and 10. BAT sympathetic innervation was enhanced from P6 to P10, and exogenous NGF, NRG4, and S100b stimulated neurite outgrowth from P6 sympathetic neurons. Endogenous BAT protein stores and/or gene expression of NRG4, S100b, and calsyntenin-3ß (which may regulate S100b secretion) remained high and constant during development. However, endogenous NGF was low and ngf mRNA was undetectable. Conditioned media (CM) from cultured P10 BAT slices stimulated neurite outgrowth from sympathetic neurons in vitro, which was inhibited by antibodies against all three growth factors. P10 CM had significant amounts of secreted NRG4 and S100b protein, but not NGF. By contrast, BAT slices from cold-acclimated adults released significant amounts of all three factors relative to thermoneutral controls. These data suggest that although neurotrophic batokines regulate sympathetic innervation in vivo, their relative contributions differ depending on the life stage. They also provide novel insights into the regulation of BAT remodeling and BAT's secretory role, both of which are critical to our understanding of mammalian energy homeostasis.NEW & NOTEWORTHY In altricial Peromyscus mice, the developmental shift to endothermy accompanies the establishment of the brown adipose tissue sympathetic neural network. Cultured slices of neonatal BAT secreted high quantities of two predicted neurotrophic batokines: S100b and neuregulin-4, but surprisingly low levels of the classic neurotrophic factor, NGF. Despite low NGF, neonatal BAT-conditioned media was highly neurotrophic. Cold-exposed adults use all three factors to dramatically remodel BAT, suggesting that BAT-neuron communication is life-stage dependent.

COVID-19 vaccine safety in Scotland - background rates of adverse events of special interest.

OBJECTIVES: Mass COVID-19 vaccination commenced in December 2020 in Scotland. Monitoring vaccine safety relies on accurate background incidence rates (IRs) for health outcomes potentially associated with vaccination. This study aimed to quantify IRs in Scotland of adverse events of special interest (AESI) potentially associated with COVID-19 vaccination. STUDY DESIGN AND METHODS: IRs and 95% confidence intervals (CIs) for 36 AESI were calculated retrospectively for the pre-COVID-19 pandemic period (01 January 2015-31 December 2019) and the COVID-19 pandemic period (01 April 2020-30 November 2020), with age-sex stratification, and separately by calendar month and year. Incident cases were determined using International Classification of Diseases-10th Revision (ICD-10)-coded hospitalisations. RESULTS: Prepandemic population-wide IRs ranged from 0.4 (0.3-0.5 CIs) cases per 100,000 person-years (PYRS) for neuromyelitis optica to 478.4 (475.8-481.0 CIs) cases per 100,000 PYRS for acute renal failure. Pandemic population-wide IRs ranged from 0.3 (0.2-0.5 CIs) cases per 100,000 PYRS for Kawasaki disease to 483.4 (473.2-493.7 CIs) cases per 100,000 PYRS for acute coronary syndrome. All AESI IRs varied by age and sex. Ten AESI (acute coronary syndrome, acute myocardial infarction, angina pectoris, heart failure, multiple sclerosis, polyneuropathies and peripheral neuropathies, respiratory failure, rheumatoid arthritis and polyarthritis, seizures and vasculitis) had lower pandemic than prepandemic period IRs overall. Only deep vein thrombosis and pulmonary embolism had a higher pandemic IR. CONCLUSION: Lower pandemic IRs likely resulted from reduced health-seeking behaviours and healthcare provision. Higher IRs may be associated with SARS-CoV-2 infections. AESI IRs will facilitate future vaccine safety studies in Scotland.

Successes and challenges in using machine-learned activation energies in kinetic simulations.

The prediction of the thermodynamic and kinetic properties of chemical reactions is increasingly being addressed by machine-learning (ML) methods, such as artificial neural networks (ANNs). While a number of recent studies have reported success in predicting chemical reaction activation energies, less attention has been focused on how the accuracy of ML predictions filters through to predictions of macroscopic observables. Here, we consider the impact of the uncertainty associated with ML prediction of activation energies on observable properties of chemical reaction networks, as given by microkinetics simulations based on ML-predicted reaction rates. After training an ANN to predict activation energies, given standard molecular descriptors for reactants and products alone, we performed microkinetics simulations of three different prototypical reaction networks: formamide decomposition, aldol reactions, and decomposition of 3-hydroperoxypropanal. We find that the kinetic modeling predictions can be in excellent agreement with corresponding simulations performed with ab initio calculations, but this is dependent on the inherent energetic landscape of the networks. We use these simulations to suggest some guidelines for when ML-based activation energies can be reliable and when one should take more care in applications to kinetics modeling.

Investigating the association between COVID-19 vaccination and care home outbreak frequency and duration.

OBJECTIVES: At the end of 2020, many countries commenced a vaccination programme against SARS-CoV-2. Public health authorities aim to prevent and interrupt outbreaks of infectious disease in social care settings. We aimed to investigate the association between the introduction of the vaccination programme and the frequency and duration of COVID-19 outbreaks in Northern Ireland (NI). STUDY DESIGN: We undertook an ecological study using routinely available national data. METHODS: We used Poisson regression to measure the relationship between the number of RT-PCR confirmed COVID-19 outbreaks in care homes, and as a measure of community COVID-19 prevalence, the Office for National Statistics COVID-19 Infection Survey estimated the number of people testing positive for COVID-19 in NI. We estimated the change in this relationship and estimated the expected number of care home outbreaks in the absence of the vaccination programme. A Cox proportional hazards model estimated the hazard ratio of a confirmed COVID-19 care home outbreak closure. RESULTS: Care home outbreaks reduced by two-thirds compared to expected following the introduction of the vaccination programme, from a projected 1625 COVID-19 outbreaks (95% prediction interval 1553-1694) between 7 December 2020 and 28 October 2021 to an observed 501. We estimated an adjusted hazard ratio of 2.53 of the outbreak closure assuming a 21-day lag for immunity. CONCLUSIONS: These findings describe the association of the vaccination with a reduction in outbreak frequency and duration across NI care homes. This indicates probable reduced harm and disruption from COVID-19 in social care settings following vaccination. Future research using individual level data from care home residents will be needed to investigate the effectiveness of the vaccines and the duration of their effects.

Cost-effectiveness of bariatric surgery and non-surgical weight management programmes for adults with severe obesity: a decision analysis model.

OBJECTIVES: To determine the most cost-effective weight management programmes (WMPs) for adults, in England with severe obesity (BMI ≥ 35 kg/m2), who are more at risk of obesity related diseases. METHODS: An economic evaluation of five different WMPs: 1) low intensity (WMP1); 2) very low calorie diets (VLCD) added to WMP1; 3) moderate intensity (WMP2); 4) high intensity (Look AHEAD); and 5) Roux-en-Y gastric bypass (RYGB) surgery, all compared to a baseline scenario representing no WMP. We also compare a VLCD added to WMP1 vs. WMP1 alone. A microsimulation decision analysis model was used to extrapolate the impact of changes in BMI, obtained from a systematic review and meta-analysis of randomised controlled trials (RCTs) of WMPs and bariatric surgery, on long-term risks of obesity related disease, costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) measured as incremental cost per QALY gained over a 30-year time horizon from a UK National Health Service (NHS) perspective. Sensitivity analyses explored the impact of long-term weight regain assumptions on results. RESULTS: RYGB was the most costly intervention but also generated the lowest incidence of obesity related disease and hence the highest QALY gains. Base case ICERs for WMP1, a VLCD added to WMP1, WMP2, Look AHEAD, and RYGB compared to no WMP were £557, £6628, £1540, £23,725 and £10,126 per QALY gained respectively. Adding a VLCD to WMP1 generated an ICER of over £121,000 per QALY compared to WMP1 alone. Sensitivity analysis found that all ICERs were sensitive to the modelled base case, five year post intervention cessation, weight regain assumption. CONCLUSIONS: RYGB surgery was the most effective and cost-effective use of scarce NHS funding resources. However, where fixed healthcare budgets or patient preferences exclude surgery as an option, a standard 12 week behavioural WMP (WMP1) was the next most cost-effective intervention.

Informing the public health response to COVID-19: a systematic review of risk factors for disease, severity, and mortality.

BACKGROUND: Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) has challenged public health agencies globally. In order to effectively target government responses, it is critical to identify the individuals most at risk of coronavirus disease-19 (COVID-19), developing severe clinical signs, and mortality. We undertook a systematic review of the literature to present the current status of scientific knowledge in these areas and describe the need for unified global approaches, moving forwards, as well as lessons learnt for future pandemics. METHODS: Medline, Embase and Global Health were searched to the end of April 2020, as well as the Web of Science. Search terms were specific to the SARS-CoV-2 virus and COVID-19. Comparative studies of risk factors from any setting, population group and in any language were included. Titles, abstracts and full texts were screened by two reviewers and extracted in duplicate into a standardised form. Data were extracted on risk factors for COVID-19 disease, severe disease, or death and were narratively and descriptively synthesised. RESULTS: One thousand two hundred and thirty-eight papers were identified post-deduplication. Thirty-three met our inclusion criteria, of which 26 were from China. Six assessed the risk of contracting the disease, 20 the risk of having severe disease and ten the risk of dying. Age, gender and co-morbidities were commonly assessed as risk factors. The weight of evidence showed increasing age to be associated with severe disease and mortality, and general comorbidities with mortality. Only seven studies presented multivariable analyses and power was generally limited. A wide range of definitions were used for disease severity. CONCLUSIONS: The volume of literature generated in the short time since the appearance of SARS-CoV-2 has been considerable. Many studies have sought to document the risk factors for COVID-19 disease, disease severity and mortality; age was the only risk factor based on robust studies and with a consistent body of evidence. Mechanistic studies are required to understand why age is such an important risk factor. At the start of pandemics, large, standardised, studies that use multivariable analyses are urgently needed so that the populations most at risk can be rapidly protected. REGISTRATION: This review was registered on PROSPERO as CRD42020177714 .

Assessing and rationalizing the performance of Hessian update schemes for reaction path Hamiltonian rate calculations.

The reaction path Hamiltonian (RPH) can be used to calculate chemical reaction rate constants, going beyond transition-state theory in taking account of recrossing by providing an approximation to the dynamic transmission coefficient. However, the RPH necessitates the calculation of the Hessian matrix at a number of points along the minimum energy path; the associated computational cost stands as a bottleneck in RPH calculations, especially if one is interested in using high-accuracy electronic structure methods. In this work, four different Hessian update schemes (symmetric rank-1, Powell-symmetric Broyden, Bofill, and TS-BFGS updates) are assessed to see whether or not they reliably reproduce calculated transmission coefficients for three different chemical reactions. Based on the reactions investigated, the symmetric rank-1 Hessian update was the least appropriate for RPH construction, giving different transmission coefficients from the standard analytical Hessian approach, as well as inconsistent frequencies and coupling properties. The Bofill scheme, the Powell-symmetric Broyden scheme, and the TS-BFGS scheme were the most reliable Hessian update methods, with transmission coefficients that were in good agreement with those calculated by the standard RPH calculations. The relative accuracy of the different Hessian update schemes is further rationalized by investigating the approximated Coriolis and curvature coupling terms along the reaction-path, providing insight into when these schemes would be expected to work well. Furthermore, the associated computational cost associated with the RPH calculations was substantially reduced by the tested update schemes. Together, these results provide useful rules-of-thumb for using Hessian update schemes in RPH simulations.

Enhanced surveillance of COVID-19 in Scotland: population-based seroprevalence surveillance for SARS-CoV-2 during the first wave of the epidemic.

OBJECTIVES: The impact of the COVID-19 pandemic in Scotland has been amongst the most severe in Europe. Serological surveillance is critical to determine the overall extent of infection across populations and to inform the public health response. This study aimed to estimate the proportion of people who have antibodies to SARS-CoV-2 ('seroprevalence') in the general population of Scotland and to see if this changes over time. STUDY DESIGN/METHODS: Between International Organization for Standardization (ISO) week 17 (i.e. week commencing 20th April) and ISO week 25 (week commencing 15 June), 4751 residual blood samples were obtained from regional biochemistry laboratories in six participating regional health authority areas covering approximately 75% of the Scottish population. Samples were tested for the presence of anti-SARS-CoV-2 IgG antibodies using the LIAISON®SARS-CoV-2 S1/S2 IgG assay (DiaSorin, Italy). Seroprevalence rates were adjusted for the sensitivity and specificity of the assay using Bayesian methods. RESULTS: The combined adjusted seroprevalence across the study period was 4.3% (95% confidence interval: 4.2%-4.5%). The proportion varied each week between 1.9% and 6.8% with no difference in antibody positivity by age, sex or geographical area. CONCLUSIONS: At the end of the first wave of the COVID-19 pandemic, only a small fraction of the Scottish population had antibodies to SARS-CoV-2. Control of COVID-19 requires the ability to detect asymptomatic and mild infections that would otherwise remain undetected through existing surveillance systems. This is important to determine the true number of infections within the general population which, in turn, can help to understand transmission, inform control measures and provide a denominator for the estimation of severity measures such as the proportion of infected people who have been hospitalised and/or have died.

National population prevalence of antibodies to SARS-CoV-2 in Scotland during the first and second waves of the COVID-19 pandemic.

OBJECTIVES: Studies that measure the prevalence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ('seroprevalence') are essential to understand population exposure to SARS-CoV-2 among symptomatic and asymptomatic individuals. We aimed to measure seroprevalence in the Scottish population over the course of the COVID-19 pandemic - from before the first recorded case in Scotland through to the second pandemic wave. STUDY DESIGN: The study design of this study is serial cross sectional. METHODS: We tested 41,477 residual samples retrieved from primary and antenatal care settings across Scotland for SARS-CoV-2 antibodies over a 12-month period from December 2019-December 2020 (before rollout of COVID-19 vaccination). Five-weekly rolling seroprevalence estimates were adjusted for the sensitivity and specificity of the assays and weighted to reference populations. Temporal trends in seroprevalence estimates and weekly SARS-CoV-2 notifications were compared. RESULTS: Five-weekly rolling seroprevalence rates were 0% until the end of March, when they increased contemporaneously with the first pandemic wave. Seroprevalence rates remained stable through the summer (range: 3%-5%) during a period of social restrictions, after which they increased concurrently with the second wave, reaching 9.6% (95% confidence interval [CI]: 8.4%-10.8%) in the week beginning 28th December in 2020. Seroprevalence rates were lower in rural vs. urban areas (adjusted odds ratio [AOR]: 0.70, 95% CI: 0.61-0.79) and among individuals aged 20-39 years and 60 years and older (AOR: 0.74, 95% CI: 0.64-0.86; AOR: 0.80, 95% CI: 0.69-0.91, respectively) relative to those aged 0-19 years. CONCLUSIONS: After two waves of the COVID-19 pandemic, less than one in ten individuals in the Scottish population had antibodies to SARS-CoV-2. Seroprevalence may underestimate the true population exposure as a result of waning antibodies among individuals who were infected early in the first wave.

National population prevalence of antibodies to SARS-CoV-2 among pregnant women in Scotland during the second wave of the COVID-19 pandemic: a prospective national serosurvey.

OBJECTIVES: This study aimed to determine SARS-CoV-2 seroprevalence among pregnant women in the Scottish population during the second wave of the COVID-19 pandemic. STUDY DESIGN: Prospective national serosurvey. METHODS: We tested 13,428 residual samples retrieved from pregnant women participating in the first trimester combined ultrasound and biochemical screening for fetal trisomy across Scotland for SARS-CoV-2 antibodies over a 6-month period from November 2020 to April 2021. Seroprevalence estimates were adjusted for the sensitivity and specificity of the assays and weighted to reference populations. RESULTS: Seroprevalence rates in the antenatal samples significantly increased from 5.5% (95% confidence interval [CI] 4.7%-6.5%) in the 5-week period up to and including International Organization for Standardization (ISO) Week 51 (w/b Monday 14 December 2020) to 11.3% (95% CI 10.1%-12.6%) in the 5-week period up to and including ISO Week 14 (w/b Monday 5 April 2021). Increasing seroprevalence trends across the second wave were observed among all age groups. CONCLUSIONS: By the end of the second wave of the COVID-19 pandemic, approximately one in 10 women tested around the end of the first trimester of pregnancy had antibodies to SARS-CoV-2, suggesting that the vast majority were still susceptible to COVID-19 as they progressed to the later stages of pregnancy, when risks from infection are elevated for both mother and baby.

A systematic review of UK-based long-term nonsurgical interventions for people with severe obesity (BMI ≥35 kg m-2 ).

INTRODUCTION: The aim of this project was to systematically review UK evidence on the effectiveness of long-term (≥12 months) weight management services (WMSs) for weight loss and weight maintenance for adults (≥16 years) with severe obesity (body mass index ≥35 kg m-2 ), who would generally be eligible for Tier 3 services. METHODS: Four data sources were searched from 1999 to October 2018. RESULTS: Our searches identified 20 studies, mostly noncomparative studies: 10 primary care interventions, nine in secondary care specialist weight management clinics and one commercial setting intervention. A programme including a phase of low energy formula diet (810-833 kcal day-1 ) showed the largest mean (SD) weight change at 12 months of -12.4 (11.4) kg for complete cases, with 25.3% dropout. Limitations or differences in evaluation and reporting (particularly for denominators), unclear dropout rates, and differences between participant groups in terms of comorbidities and psychological characteristics, made comparisons between WMSs and inferences challenging. CONCLUSIONS: There is a persistent and clear need for guidance on long-term weight data collection and reporting methods to allow comparisons across studies and services for participants with severe obesity. Data could also include quality of life, clinical outcomes, adverse events, costs and economic outcomes. A randomised trial comparison of National Health Service Tier 3 services with commercial WMSs would be of value.

The Future of Neurocritical Care Research: Proceedings and Recommendations from the Fifth Neurocritical Care Research Network Conference.

The Fifth Neurocritical Care Research Network (NCRN) Conference held in Boca Raton, Florida, in September of 2018 was devoted to challenging the current status quo and examining the role of the Neurocritical Care Society (NCS) in driving the science and research of neurocritical care. The aim of this in-person meeting was to set the agenda for the NCS's Neurocritical Care Research Central, which is the overall research arm of the society. Prior to the meeting, all 103 participants received educational content (book and seminar) on the 'Blue Ocean Strategy®,' a concept from the business world which aims to identify undiscovered and uncontested market space, and to brainstorm innovative ideas and methods with which to address current challenges in neurocritical care research. Three five-member working groups met at least four times by teleconference prior to the in-person meeting to prepare answers to a set of questions using the Blue Ocean Strategy concept as a platform. At the Fifth NCRN Conference, these groups presented to a five-member jury and all attendees for open discussion. The jury then developed a set of recommendations for NCS to consider in order to move neurocritical care research forward. We have summarized the topics discussed at the conference and put forward recommendations for the future direction of the NCRN and neurocritical care research in general.

Coumestrol Confers Partial Resistance in Soybean Plants Against Cercospora Leaf Blight.

Although previous research showed that the purple symptom of Cercospora leaf blight (CLB) is associated with lower biomass of Cercospora cf. flagellaris and lower concentrations of cercosporin, a reactive oxygen species producer, as compared with blighted leaves, the hypothesis that the purple symptom is a plant reaction to the pathogen has never been tested. In this study, we demonstrated that high levels of coumestrol (COU) were associated with purple symptoms of CLB and that COU has strong antioxidant activity. Additionally, we found that COU is restricted to the pigmented areas of purple leaves, and the pigmentation is restricted to the adaxial surfaces, suggesting that COU may be acting as a sunscreen. Even though COU is associated with the purple leaf symptom, this coumestan is not the direct cause of discoloration in that COU is colorless. Quantification of chlorophyll a and b and total carotenoids suggested that blighted but not purple or asymptomatic leaves were undergoing photooxidative stress. Because the purple symptom is associated with high COU concentrations, lower biomass of C. cf. flagellaris, and lower cercosporin concentrations, we conclude that the purple symptom is a disease resistance reaction, mediated in part by COU, which provides a high level of antioxidant activity and, hence, partial resistance.

Development of a portable blood salvage and autotransfusion technology to enhance survivability of personnel requiring major medical interventions in austere or military environments.

INTRODUCTION: Uncontrolled haemorrhage is the leading cause of death on the battlefield, and two-thirds of these deaths result from non-compressible haemorrhage. Blood salvage and autotransfusion represent an alternative to conventional blood transfusion techniques for austere environments, potentially providing blood to the casualty at point of injury. The aim of this paper is to describe the design, development and initial proof-of-concept testing of a portable blood salvage and autotransfusion technology to enhance survivability of personnel requiring major medical interventions in austere or military environments. METHOD: A manually operable, dual-headed pump was developed that removes blood from site of injury to a collection reservoir (upper pump) and back to casualty (lower pump). Theoretical flow rate calculations determined pump configuration and a three-dimensionally printed peristaltic pump was manufactured. Flow rates were tested with fresh bovine blood under laboratory conditions representative of the predicted clinical environment. RESULTS: Mathematical modelling suggested flow rates of 3.6 L/min and 0.57 L/min for upper and lower pumps. Using fresh bovine blood, flow rates produced were 2.67 L/min and 0.43 L/min. To mimic expected battlefield conditions, upper suction pump flow rate was calculated using a blood/air mixture. CONCLUSION: The authors believe that this technology can potentially enhance survivability for casualties in austere and deployed military settings through autotransfusion and cell concentration. It reduces negative effects of blood donation on the conventional donor pool, and potentially negates the logistical constraints associated with allogenic transfusions.

Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: link to impulsivity in methamphetamine users.

Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC) and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than that in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between the midbrain and striatum, orbitofrontal cortex and insula in methamphetamine-dependent participants, but a positive relationship in the control group. In Study 2, an interaction of the group with RSFC on impulsivity was observed. Methamphetamine-dependent users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect the system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals.

Reduction in colposcopy workload and associated clinical activity following human papillomavirus (HPV) catch-up vaccination programme in Scotland: an ecological study.

OBJECTIVE: To measure patterns of clinical activity at colposcopy before and after vaccinated women entered the Scottish Cervical Screening Programme (SCSP). DESIGN: Population-based observational study using nationally collected data. SETTING: Scottish colposcopy clinics. SAMPLE: All women with a date of birth on or after 1 January 1985 who attended colposcopy in Scotland between 2008 and 2014. METHODS: Routinely collected data from the Scottish National Colposcopy Clinical Information Audit System (NCCIAS) were extracted, including: referral criteria, referral cervical cytology, colposcopic findings, clinical procedures, and histology results. Analysis was restricted to those referred to colposcopy at age 20 or 21 years. MAIN OUTCOME MEASURES: Referral criteria, positive predictive value of colposcopy, default rates, and rates of cervical biopsies and treatments. RESULTS: A total of 7372 women referred for colposcopy at age 20 or 21 years were identified. There was a downward trend in the proportion of those referred with abnormal cytology (2008/9, 91.0%; 2013/14, 90.3%; linear trend P = 0.03). Women were less likely to have diagnostic or therapeutic interventions. The proportion with no biopsy (2008/9, 19.5%; 2013/14, 26.9%; linear trend P < 0.0001) and no treatment (2008/9, 74.9%; 2013/14, 91.8%; linear trend P < 0.0001) increased over the period of observation. CONCLUSIONS: A reduction in clinical activity related to abnormal screening referrals is likely to be associated with the human papillomavirus (HPV) catch-up immunisation programme. Referral criteria and the service provision of colposcopy needs to be planned carefully, taking account of the increasing number of women who have been immunised against HPV that will be entering cervical screening programmes worldwide. TWEETABLE ABSTRACT: Colposcopy referral criteria and service planning need attention following HPV immunisation programme.

The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch-up vaccine programme: a two-centre observational study.

OBJECTIVE: To determine whether human papillomavirus (HPV) immunisation has affected the prevalence of HPV genotypes and colposcopic features of cervical intraepithelial neoplasia (CIN) in young women referred for colposcopy. DESIGN: A two-centre observational study including vaccinated and unvaccinated women. SETTING: Colposcopy clinics serving two health regions in Scotland, UK. POPULATION: A total of 361 women aged 20-25 years attending colposcopy following an abnormal cervical cytology result at routine cervical screening. METHODS: Cervical samples were obtained from women for HPV DNA genotyping and mRNA E6/E7 expression of HPV 16, 18, 31, 33, and 45. Demographic data, cytology, and histology results and colposcopic features were recorded. Chi-square analysis was conducted to identify associations between vaccine status, HPV genotypes, and colposcopic features. MAIN OUTCOME MEASURES: Colposcopic features, HPV genotypes, mRNA expression, and cervical histology. RESULTS: The prevalence of HPV 16 was significantly lower in the vaccinated group (8.6%) compared with the unvaccinated group (46.7%) (P = 0.001). The number of cases of CIN2+ was significantly lower in women who had been vaccinated (P = 0.006). The HPV vaccine did not have a statistically significant effect on commonly recognised colposcopic features, but there was a slight reduction in the positive predictive value (PPV) of colposcopy for CIN2+, from 74% (unvaccinated) to 66.7% (vaccinated). CONCLUSIONS: In this group of young women with abnormal cytology referred to colposcopy, HPV vaccination via a catch-up programme reduced the prevalence of CIN2+ and HPV 16 infection. The reduced PPV of colposcopy for the detection of CIN2+ in women who have been vaccinated is at the lower acceptable level of the UK national cervical screening programme guidelines. TWEETABLE ABSTRACT: Reduction of hrHPV positivity and CIN in immunised women consistent with lower PPV of colposcopy for CIN2+.

HPV immunisation and increased uptake of cervical screening in Scottish women; observational study of routinely collected national data.

BACKGROUND: To measure the uptake of first invitation to cervical screening by vaccine status in a population-based cohort offered HPV immunisation in a national catch-up campaign. METHODS: A retrospective observational study of routinely collected data from the Scottish Cervical Screening Programme. Data were extracted and linked from the Scottish Cervical Call Recall System, the Scottish Population Register and the Scottish Index of Multiple Deprivation. Records from 201 023 women born between 1 January 1988 and 30 September 1993 were assessed. Women born in or after 1990 were eligible for the national catch-up programme of HPV immunisation. Attendance for screening was within 12 months of the first invitation at age 20 years. RESULTS: There was a significant decline in overall attendance from the 1988 cohort to the 1993 cohort with the adjusted attendance ratio of the 1988 cohort being 1.49 times (95% CI 1.46-1.52) that of the 1993 cohort. Immunisation compensated for this decrease in uptake with unvaccinated individuals having a reduced ratio of attendance compared with those fully vaccinated (RR=0.65, 95% CI 0.64-0.65). Not taking up the opportunity for HPV immunisation was associated with an attendance for screening below the trend line for all women before the availability of HPV immunisation. CONCLUSIONS: HPV immunisation is not associated with the reduced attendance for screening that had been feared. Immunised women in the catch-up cohorts appear to be more motivated to attend than unimmunised women, but this may be a result of a greater awareness of health issues. These results, while reassuring, may not be reproduced in routinely immunised women. Continued monitoring of attendance for the first smear and subsequent routine smears is needed.