The impact of loss to follow-up in the Dutch organised HPV-based cervical cancer screening programme.

Loss to follow-up (LTFU) within cervical screening programmes can result in missed clinically relevant lesions, potentially reducing programme effectiveness. To examine the health impact of losing women during the screening process, we determined the proportion of women LTFU per step of the Dutch hrHPV-based screening programme. We then determined the probability of being LTFU by age, screening history and sampling method (self- or clinician-sampled) using logistic regression analysis. Finally, we estimated the number of missed CIN2+/3+ lesions per LTFU moment by using the CIN-risk in women compliant with follow-up. Data from the Dutch nationwide pathology databank (Palga) was used. Women eligible for screening in 2017 and 2018 were included (N = 840,428). For clinician collected (CC) samples, the highest proportion LTFU was found following 'referral advice for colposcopy' (5.5% after indirect referral; 3.8% after direct referral). For self-sampling, the highest proportions LTFU were found following the advice for repeat cytology (13.6%) and after referral advice for colposcopy (8.2% after indirect referral; 4.3% after direct referral). Self-sampling users and women with no screening history had a higher LTFU-risk (OR: 3.87, CI: 3.55-4.23; OR: 1.39, CI: 1.20-1.61) compared to women that used CC sampling and women that have been screened before, respectively. Of all women LTFU in 2017/18, the total number of potentially missed CIN2+ was 844 (21% of women LTFU). Most lesions were missed after 'direct referral for colposcopy' (N = 462, 11.5% of women LTFU). So, this indicates a gap between the screening programme and clinical care which requires further attention, by improving monitoring of patients after referral.

Resilience of the Dutch HPV-based cervical screening programme during the COVID-19 pandemic.

OBJECTIVES: Organisation of a screening programme influences programme resilience to a disruption as COVID-19. Due to COVID-19, the Dutch human papillomavirus-based cervical screening programme was temporarily suspended. Afterwards, multiple measures have been taken to catch-up participation. This study aimed to investigate programme resilience by examining the effect of COVID-19 and programme measures taken on participation in cervical screening. STUDY DESIGN: Observational cohort study. METHODS: Data from the national screening registry and Dutch nationwide pathology databank (Palga) were used on invitations and follow-up in 2018/2019 (pre-COVID) and 2020 (COVID). Sending invitations, reminders and self-sampling kits were suspended from March to July 2020. Main outcome measures include distribution of participant characteristics (age, region and screening history), participation rates by age and region, time between invitation and participation (i.e. response time) and self-sampling use per month. RESULTS: Participation rate was significantly lower in 2020 (49.8%) compared to 2018/19 (56.8%, P < 0.001), in all ages and regions. Compared to 2018/19, participation rates decreased most in women invited from January to March 2020 (-6.7%, -9.1% and -10.4%, respectively). From August, participation rates started to recover (difference between -0.8% and -2.7%). Median response time was longer in February and March (2020: 143 and 173 days; 2018/19: 53 and 55 days) and comparable from July onwards (median difference 0-6 days). Self-sampling use was higher in 2020 (16.3%) compared to 2018/19 (7.6%). CONCLUSIONS: The pandemic impacted participation rates in the Dutch cervical screening programme, especially of women invited before the programme pause. Implementation of self-sampling in national cervical screening programmes could increase participation rates and could serve as an alternative screening method in times of exceptional health care circumstances, such as a pandemic. Due to the well-organised programme and measures taken to catch-up participation, the impact of COVID-19 on the screening programme remained small.

Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischemia.

The bioactive lipid intermediate palmitoyl CoA (PCoA) can inhibit mitochondrial ADP/ATP transport, though the physiological relevance of this regulation remains unclear. We questioned whether myocardial ischemia provides a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial, and secondly, whether the chronically elevated lipid content within the diabetic heart could make mitochondria less sensitive to the effects of PCoA. PCoA acutely decreased ADP-stimulated state 3 respiration and increased the apparent Km for ADP twofold. The half maximal inhibitory concentration (IC50 ) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in diabetic mitochondria, with no significant difference in the Km for ADP in the presence of PCoA, and an increase in the IC50 to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, regenerating the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischemia, however, this beneficial effect was blunted in diabetic mitochondria. Finally, using 31 P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischemia, with a threefold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism seen during myocardial ischemia in the diabetic heart.

Increased Risk of High-grade Cervical Neoplasia in Women with Inflammatory Bowel Disease: A Case-controlled Cohort Study.

BACKGROUND AND AIMS: Women with inflammatory bowel disease [IBD] may be at higher risk for cervical intraepithelial neoplasia [CIN]. However, data are conflicting. The aim of this study was to assess the risk of high-grade dysplasia and cancer [CIN2+] in IBD women and identify risk factors. METHODS: Clinical data from adult IBD women in a multicentre Dutch IBD prospective cohort [PSI] from 2007 onwards were linked to cervical cytology and histology records from the Dutch nationwide cytology and pathology database [PALGA], from 2000 to 2016. Patients were frequency-matched 1:4 to a general population cohort. Standardised detection rates [SDR] were calculated for CIN2+. Longitudinal data were assessed to calculate CIN2+ risk during follow-up using incidence rate ratios [IRR] and risk factors were identified in multivariable analysis. RESULTS: Cervical records were available from 2098 IBD women [77%] and 8379 in the matched cohort; median follow-up was 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95% confidence interval [CI] 1.05-1.52). Women with IBD had an increased risk of CIN2+ [IRR 1.66, 95% CI 1.21-2.25] and persistent or recurrent CIN during follow-up (odds ratio [OR] 1.89, 95% CI 1.06-3.38). Risk factors for CIN2+ in IBD women were smoking and disease location (ileocolonic [L3] or upper gastrointestinal [GI] [L4]). CIN2+ risk was not associated with exposure to immunosuppressants. CONCLUSIONS: Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of human papillomavirus [HPV] vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants.

Cost-effectiveness of HPV-based cervical screening based on first year results in the Netherlands: a modelling study.

OBJECTIVE: We aim to compare the cost-effectiveness of the old cytology programme with the new high-risk human papillomavirus (hrHPV) screening programme, using performance indicators from the new Dutch hrHPV screening programme. DESIGN: Model-based cost-effectiveness analysis. SETTING: The Netherlands. POPULATION: Dutch 30-year-old unvaccinated females followed up lifelong. METHODS: We updated the microsimulation screening analysis (MISCAN) model using the most recent epidemiological and screening data from the Netherlands. We simulated both screening programmes, using the screening behaviour and costs observed in each programme. Sensitivity analyses were performed on screening behaviour, utility losses and discount rates. MAIN OUTCOME MEASURES: Cervical cancer incidence and mortality rates, number of screening tests and repeat tests, colposcopy referrals by lesion grade, costs from a societal perspective, quality-adjusted life years (QALYs) gained and cost-effectiveness. RESULTS: The new Dutch cervical cancer screening programme decreased the cervical cancer mortality by 4% and the incidence by 1% compared with the old programme. Colposcopy referrals of women without cervical intra-epithelial neoplasia grade 2 or worse, increased by 172%, but 13% more QALYs were still achieved. Total costs were reduced by 21%, mainly due to fewer screening tests. Per QALY gained, the hrHPV programme cost 46% less (€12,225) than the cytology programme (€22,678), and hrHPV-based screening remained more cost-effective in all sensitivity analyses. CONCLUSIONS: The hrHPV-based screening programme was found to be more effective and cost-effective than the cytology programme. Alternatives for the current triage strategy should be considered to lower the number of unnecessary referrals. TWEETABLE ABSTRACT: First results after implementation confirm that HPV screening is more cost-effective than cytology screening.

Repeat participation in annual cross-sectional surveys of drug users and its implications for analysis.

OBJECTIVE: We sought to establish the extent of repeat participation in a large annual cross-sectional survey of people who inject drugs and assess its implications for analysis. RESULTS: We used "porn star names" (the name of each participant's first pet followed by the name of the first street in which they lived) to identify repeat participation in three Australian Illicit Drug Reporting System surveys. Over 2013-2015, 2468 porn star names (96.2%) appeared only once, 88 (3.4%) twice, and nine (0.4%) in all 3 years. We measured design effects, based on the between-cluster variability for selected estimates, of 1.01-1.07 for seven key variables. These values indicate that the complex sample is (e.g.) 7% less efficient in estimating prevalence of heroin use (ever) than a simple random sample, and 1% less efficient in estimating number of heroin overdoses (ever). Porn star names are a useful means of tracking research participants longitudinally while maintaining their anonymity. Repeat participation in the Australian Illicit Drug Reporting System is low (less than 5% per annum), meaning point-prevalence and effect estimation without correction for the lack of independence in observations is unlikely to seriously affect population inference.

Critical analysis of forensic cut-offs and legal thresholds: A coherent approach to inference and decision.

In this paper we critically discuss the definition and use of cut-off values by forensic scientists, for example in forensic toxicology, and point out when and why such values - and ensuing categorical conclusions - are inappropriate concepts for helping recipients of expert information with their questions of interest. Broadly speaking, a cut-off is a particular value of results of analyses of a target substance (e.g., a toxic substance or one of its metabolites in biological sample from a person of interest), defined in a way such as to enable scientists to suggest conclusions regarding the condition of the person of interest. The extent to which cut-offs can be reliably defined and used is not unanimously agreed within the forensic science community, though many practitioners - especially in operational laboratories - rely on cut-offs for reasons such as ease of use and simplicity. In our analysis, we challenge this practice by arguing that choices made for convenience should not be to the detriment of balance and coherence. To illustrate our discussion, we will choose the example of alcohol markers in hair, used widely by forensic toxicologists to reach conclusions regarding the drinking behaviour of individuals. Using real data from one of the co-authors' own work and recommendations of cut-offs published by relevant professional organisations, we will point out in what sense cut-offs are incompatible with current evaluative guidelines (e.g., [31]) and show how to proceed logically without cut-offs by using a standard measure for evidential value. Our conclusions run counter to much current practice, but are inevitable given the inherent definitional and conceptual shortcomings of scientific cut-offs. We will also point out the difference between scientific cut-offs and legal thresholds and argue that the latter - but not the former - are justifiable and can be dealt with in logical evaluative procedures.

Assessing individual-level needle and syringe coverage parameters and the measurement of coverage in Melbourne, Australia: methods and impacts.

Background: To assess the structure of individual-level needle and syringe coverage measurement formula, and to estimate the impact of coverage-related behaviours/parameters (instances of syringe acquisition, total syringes acquired, peer-to-peer syringe distribution, injecting frequency) on overall coverage. Methods: Data are drawn from the Melbourne (Australia) injecting drug user cohort study, 2010-16. Data from 518 participants were analysed. We used correlations to explore the relationships between coverage parameters; pooled multiple-linear regression to estimate the effect of each parameter on coverage over time; and exploratory factor analysis to assess the relevance of each parameter within the coverage formula. Results: A 1-unit increase in injecting frequency over time reduced coverage by 10.93 percentage points, almost twice as much as other coverage parameters. Factor analysis results indicated potential improvements to coverage formula structure. Conclusions: Our results suggest that reducing injecting frequency amongst people who inject drugs has the largest improvement in coverage levels, indicating harm reduction services should prioritize it. We also demonstrate that coverage measurement has been inconsistent to date. We sought to refine the method to assist in generating comparable research.

Comprehensive two-dimensional gas chromatography-mass spectrometry of complex mixtures of anaerobic bacterial metabolites of petroleum hydrocarbons.

Anaerobic biotransformation of petroleum hydrocarbons is an important alteration mechanism, both subsurface in geological reservoirs, in aquifers and in anoxic deep sea environments. Here we report the resolution and identification, by comprehensive two-dimensional gas chromatography-mass spectrometry (GC×GC-MS), of complex mixtures of aromatic acid and diacid metabolites of the anaerobic biodegradation of many crude oil hydrocarbons. An extended range of metabolites, including alkylbenzyl, alkylindanyl, alkyltetralinyl, alkylnaphthyl succinic acids and alkyltetralin, alkylnaphthoic and phenanthrene carboxylic acids, is reported in samples from experiments conducted under sulfate-reducing conditions in a microcosm over two years. The range of metabolites identified shows that the fumarate addition mechanism applies to the alteration of hydrocarbons with up to C8 alkylation in monoaromatics and that functionalisation of up to three ring aromatic hydrocarbons with at least C1 alkylation occurs. The GC×GC-MS method might now be applied to the identification of complex mixtures of metabolites in samples from real environmental oil spills.

The meaning of justified subjectivism and its role in the reconciliation of recent disagreements over forensic probabilism.

In this paper we reply to recent comments in this Special Issue according to which subjective probability is not considered to be a concept fit for use in forensic evaluation and expert reporting. We identify the source of these criticisms to lie in a misunderstanding of subjective probability as unconstrained subjective probability; a lack of constraint that neither corresponds to the way in which we referred to subjective probability in our previous contributions, nor to the way in which probability assignment is understood by current evaluative guidelines (e.g., of ENFSI). Specifically, we explain that we understand subjective probability as a justified assertion, i.e. a conditional assessment based on task-relevant data and information, that may be thought of as a constrained subjective probability. This leads us to emphasise again the general conclusion that there is no gap between justified (or, reasonable) subjective probability and other concepts of probability in terms of its ability to provide assessments that are soundly based on whatever relevant information available. We also note that the challenges an expert faces in reporting probabilities apply equally to all interpretations of probability, not only to subjective probability.

HIV-1 integrase inhibitor resistance among treatment naïve patients in the West of Scotland.

BACKGROUND: Transmitted integrase inhibitor resistance is rare, with only a small number of cases reported world-wide to date. OBJECTIVES: The aim of this study was to assess whether transmitted integrase inhibitor resistance has occurred in Scotland and if so, could there be a case for performing genotypic integrase resistance testing at baseline. STUDY DESIGN: The study population consisted of 106 treatment naïve, newly diagnosed, HIV positive patients. The patient samples were collected between October 2015 and March 2016 at the time of HIV diagnosis and prior to initiation of anti-retroviral therapy. The integrase region was amplified and sequenced. RESULTS: We detected integrase inhibitor resistance (T66I/T) at baseline in one patient sample. This is a non-polymorphic mutation seen in patients receiving elvitegravir which confers high-level resistance to elvitegravir and intermediate resistance to raltegravir. A further 10 patients had accessory mutations which have minimal or no effect on susceptibility to integrase inhibitors. CONCLUSIONS: Transmitted integrase inhibitor resistance remains rare. The results of the present study do not support performing integrase resistance testing at baseline.

The consequences of understanding expert probability reporting as a decision.

In this paper we reiterate that the personalist interpretation of probability is inevitable and as least as informed as any other allegedly more 'objective' definition of probability. We also argue that the problem faced by forensic scientists, the reporting on imperfect personal knowledge, in terms of probabilities, can be reconstructed as a decision problem. Tackling this problem through a rigorous decision theoretic analysis provides further argument in support of the view that optimal probability reporting is in terms of single numbers, not intervals.

The effects of needle-sharing and opioid substitution therapy on incidence of hepatitis C virus infection and reinfection in people who inject drugs.

Although high hepatitis C virus (HCV) prevalence has been observed in people who inject drugs (PWID) for decades, research suggests incidence is falling. We examined whether PWIDs' use of opioid substitution therapy (OST) and their needle-and-syringe sharing behaviour explained HCV incidence. We assessed HCV incidence in 235 PWID in Melbourne, Australia, and performed discrete-time survival with needle-sharing and OST status as independent variables. HCV infection, reinfection and combined infection/reinfection incidences were 7·6 [95% confidence interval (CI) 4·8-11·9], 12·4 (95% CI 9·1-17·0) and 9·7 (95% CI 7·4-12·6) per 100 person-years, respectively. Needle-sharing was significantly associated with higher incidence of naive HCV infection [hazard ratio (HR) 4·9, 95% CI 1·3-17·7] but not reinfection (HR 1·85, 95% CI 0·79-4·32); however, a cross-model test suggested this difference was sample specific. Past month use of OST had non-significant protective effects against naive HCV infection and reinfection. Our data confirm previous evidence of greatly reduced HCV incidence in PWID, but not the significant protective effect of OST on HCV incidence detected in recent studies. Our findings reinforce the need for greater access to HCV testing and prevention services to accelerate the decline in incidence, and HCV treatment, management and support to limit reinfection.

Distribution of cocaine on banknotes in general circulation in England and Wales.

A study of the quantities of cocaine on banknotes in general circulation was conducted to investigate regional variations across England and Wales. No meaningful support was found for the proposition that there is regional variation in the quantities of cocaine in banknotes in general circulation in England and Wales.

Reframing the debate: A question of probability, not of likelihood ratio.

Evidential value is measured by a likelihood ratio. This ratio has two components, the probability, or probability density, of the evidence if the prosecution proposition is true and the probability (density) of the evidence if the defence proposition is true. It takes the form of a single value, even if these probabilities are subjective measures of belief of the reporting forensic scientist.

Cluster of influenza A cases in vaccinated population of adults in Virology Laboratory in Glasgow in December 2012.

BACKGROUND AND AIMS: The majority of influenza infections during the 2012/2013 influenza season in Scotland have been due to influenza A H3N2. We report an outbreak of influenza A H3N2 in a vaccinated population of adults in the Regional Virology Laboratory in Glasgow. This investigation was carried out to confirm the epidemiological link between cases. METHODS AND RESULTS: Staff with clinical symptoms of influenza-like illness were included. Samples were tested by real-time polymerase chain reaction and sequencing. Staff were interviewed to obtain information regarding symptom onset and vaccination status. Eight confirmed cases and six clinically diagnosed cases were reported, which all occurred within 4 days of a lunchtime Christmas quiz. The eight samples subtyped as H3 virus. The haemagglutinin gene in the confirmed cases was sequenced and shown to be identical. Most of the attendees had been immunised against influenza with the same vaccine batch at least 6 weeks earlier. CONCLUSION: This outbreak appears to have been an isolated incident, which arose due to a social event that provided the ideal conditions for transmission of a respiratory disease. It may have been compounded by low-vaccine effectiveness this season. Sequence data supported the epidemiological link.

Use of laboratory-based surveillance data to estimate the number of people chronically infected with hepatitis B living in Scotland.

It is paramount to understand the epidemiology of chronic hepatitis B to inform national policies on vaccination and screening/testing as well as cost-effectiveness studies. However, information on the national (Scottish) prevalence of chronic hepatitis B by ethnic group is lacking. To estimate the number of people with chronic hepatitis B in Scotland in 2009 by ethnicity, gender and age, the test data from virology laboratories in the four largest cities in Scotland were combined with estimates of the ethnic distribution of the Scottish population. Ethnicity in both the test data and the Scottish population was derived using a name-based ethnicity classification software (OnoMAP; Publicprofiler Ltd, UK). For 2009, we estimated 8720 [95% confidence interval (CI) 7490-10 230] people aged ⩾15 years were living with chronic hepatitis B infection in Scotland. This corresponds to 0·2% (95% CI 0·17-0·24) of the Scottish population aged ⩾15 years. Although East and South Asians make up a small proportion of the Scottish population, they make up 44% of the infected population. In addition, 75% of those infected were aged 15-44 years with almost 60% male. This study quantifies for the first time on a national level the burden of chronic hepatitis B infection by ethnicity, gender and age. It confirms the importance of promoting and targeting ethnic minority groups for hepatitis B testing.

Multiplex PCR testing requires a robust multi-disciplinary strategy to effectively manage identified cases of chlamydial conjunctivitis.

INTRODUCTION: Implementation of an in-house polymerase chain reaction (PCR) multiplex assay by West of Scotland Specialist Virology Centre to improve sample processing means all viral eye swabs are now routinely tested for Adenovirus, Herpes simplex, Varicella and Chlamydia. Concern was raised regarding subsequent management and sexual health attendance for Chlamydia-positive patients identified in eye casualty. METHODS: A retrospective review of virology results identified 76 Chlamydia-positive patients from 1914 eye swabs (4%) from May 2007 to April 2008. Of these results, 12 originated from Glasgow eye casualty and available clinical notes were cross-referenced with the sexual health network (Sandyford). RESULTS: Identified issues included no documentation of implications of testing, poor communication of positive results and poor referral pathways to sexual health for assessment; all leading to inadequate management. A shared care network was created to address these issues. A designated sexual health advisor was identified to improve sexual health referral, specialist assessment, standardised management and contact tracing. Re-audit showed more consistent follow-up. CONCLUSION: New PCR technology has resulted in a shared care approach to address corresponding implications of testing. Effective communication with a structured protocol and a central point of contact has improved follow-up and ensures appropriate best practice management of chlamydial conjunctivitis.

Cytokine responses in patients with mild or severe influenza A(H1N1)pdm09.

BACKGROUND: Influenza virus affects millions of people worldwide each year. More severe infection occurs in the elderly, very young and immunocompromised. In 2009, a new variant of swine origin (influenza A(H1N1)pdm09 virus) emerged that produced severe disease in young healthy adults. OBJECTIVES: The aim of this study was to determine whether cytokine concentrations are associated with clinical outcome in patients infected influenza A(H1N1)pdm09 virus. STUDY DESIGN: Plasma concentration of 32 cytokines and growth factors were measured using a multiplex bead immunoassay and conventional ELISA in four patient groups. Patients with severe and mild influenza A(H1N1)pdm09 virus infection, rhinovirus infection and healthy volunteers were investigated. In addition, serial samples of respiratory secretions from five patients with severe influenza A(H1N1)pdm09 virus infection were examined. RESULTS: The majority of cytokines measured were elevated in patients with viral respiratory infections compared to the healthy controls. Concentrations of IL-6, IL-10, IL-15, IP-10, IL-2R, HGF, ST2 and MIG were significantly higher (p<0.05) and EGF significantly lower (p=0.0001) in patients with severe influenza A(H1N1)pdm09 virus infection compared to those with mild influenza A(H1N1)pdm09 virus and rhinovirus infection. CONCLUSIONS: A number of cytokines were found to be substantially elevated in patients with severe influenza A(H1N1)pdm09 virus infection. This supports and extends other published work suggesting a role for proinflammatory cytokines in influenza-induced lung pathology. Interestingly, EGF was significantly lower in patients with severe infection suggesting it is actively suppressed. As EGF has a role in role in cell proliferation and tissue repair, it may protect the lung from host or virus mediated damage.