Schistosomiasis in Scottish travellers: public health importance of laboratory testing and the need for enhanced surveillance.

Background: Imported schistosomiasis is of significant public health importance and is likely to be underestimated since infection is often asymptomatic. We describe data from travellers residing in Scotland which includes a subset of group travellers from one of the largest Health Boards in Scotland. Methods: Clotted bloods were obtained during the period 2001-15 from a total of 8163 Scottish travellers. This included seven groups comprising of 182 travellers. Sera were examined for the presence of Schistosome species antibody at the Scottish Parasite Diagnostic and Reference Laboratory (SPDRL). Results: Of all, 25% (n = 1623) tested positive with 40% (n = 651) of those patients aged between 20 and 24 years. Although 62% (n = 1006) of those who tested positive reported travel to Africa, important information on the specific region visited was lacking in almost one-third of samples received. Overall, 62 (34%) of group travellers tested positive and 95% (n = 59) reporting travel to Africa. Conclusions: Globalization, affordable air travel and improved awareness, are likely to contribute towards the increasing number of imported schistosomiasis cases. Therefore, enhanced surveillance capturing detailed travel history and fresh water exposures will improve risk stratification, pre-travel advice and optimize testing and treatment regimes for this increasingly important parasitic disease.

Suitability of loci for multiple-locus variable-number of tandem-repeats analysis of Cryptosporidium parvum for inter-laboratory surveillance and outbreak investigations.

Cryptosporidium parvum is the major cause of livestock and zoonotically-acquired human cryptosporidiosis. The ability to track sources of contamination and routes of transmission by further differentiation of isolates would assist risk assessment and outbreak investigations. Multiple-locus variable-number of tandem-repeats (VNTR) analysis provides a means for rapid characterization by fragment sizing and estimation of copy numbers, but structured, harmonized development has been lacking for Cryptosporidium spp. To investigate potential for application in C. parvum surveillance and outbreak investigations, we studied nine commonly used VNTR loci (MSA, MSD, MSF, MM5, MM18, MM19, MS9-Mallon, GP60 and TP14) for chromosome distribution, repeat unit length and heterogeneity, and flanking region proximity and conservation. To investigate performance in vitro, we compared these loci in 14 C. parvum samples by capillary electrophoresis in three laboratories. We found that many loci did not contain simple repeat units but were more complex, hindering calculations of repeat unit copy number for standardized reporting nomenclature. However, sequenced reference DNA enabled reproducible fragment sizing and inter-laboratory allele assignation based on size normalized to that of the sequenced fragments by both single round and nested polymerase chain reactions. Additional Cryptosporidium loci need to be identified and validated for robust inter-laboratory surveillance and outbreak investigations.

Glibenclamide and metfoRmin versus stAndard care in gEstational diabeteS (GRACES): a feasibility open label randomised trial.

BACKGROUND: Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM. METHODS: We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks' gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic control, participant satisfaction and clinical outcomes. RESULTS: Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n = 13) or metformin and insulin (n = 10). Mean (SD) recruitment rate was 0.39 (0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6-90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic control to metformin and glibenclamide, with fewer blood glucose readings <3.5 mmol/l (median [IQR] difference/woman/week of treatment 0.58 [0.03-1.87]). CONCLUSIONS: A large randomised controlled trial comparing glibenclamide or insulin in combination with metformin for women with GDM would be feasible but is unlikely to be worthwhile, given the poorer glycaemic control with glibenclamide and metformin in this pilot study. The combination of metformin and glibenclamide should be reserved for women with GDM with true needle phobia or inability to use insulin therapy. TRIAL REGISTRATION: www.clinicaltrials.gov registration number:NCT02080377 February 11th 2014.

Cyclosporiasis in travellers returning to the United Kingdom from Mexico in 2017: lessons from the recent past to inform the future.

During the summers of 2015 and 2016, the United Kingdom experienced large outbreaks of cyclosporiasis in travellers returning from Mexico. As the source of the outbreaks was not identified, there is the potential for a similar outbreak to occur in 2017; indeed 78 cases had already been reported as at 27 July 2017. Early communication and international collaboration is essential to provide a better understanding of the source and extent of this recurring situation.

Cyclospora infection linked to travel to Mexico, June to September 2015.

Cyclospora cayetanensis was identified in 176 returned travellers from the Riviera Maya region of Mexico between 1 June and 22 September 2015; 79 in the United Kingdom (UK) and 97 in Canada. UK cases completed a food exposure questionnaire. This increase in reported Cyclospora cases highlights risks of gastrointestinal infections through travelling, limitations in Cyclospora surveillance and the need for improved hygiene in the production of food consumed in holiday resorts.

Polyherbal and Multimodal Treatments: Kaempferol- and Quercetin-Rich Herbs Alleviate Symptoms of Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder impairing cognition and memory in the elderly. This disorder has a complex etiology, including senile plaque and neurofibrillary tangle formation, neuroinflammation, oxidative stress, and damaged neuroplasticity. Current treatment options are limited, so alternative treatments such as herbal medicine could suppress symptoms while slowing cognitive decline. We followed PRISMA guidelines to identify potential herbal treatments, their associated medicinal phytochemicals, and the potential mechanisms of these treatments. Common herbs, including Ginkgo biloba, Camellia sinensis, Glycyrrhiza uralensis, Cyperus rotundus, and Buplerum falcatum, produced promising pre-clinical results. These herbs are rich in kaempferol and quercetin, flavonoids with a polyphenolic structure that facilitate multiple mechanisms of action. These mechanisms include the inhibition of Aß plaque formation, a reduction in tau hyperphosphorylation, the suppression of oxidative stress, and the modulation of BDNF and PI3K/AKT pathways. Using pre-clinical findings from quercetin research and the comparatively limited data on kaempferol, we proposed that kaempferol ameliorates the neuroinflammatory state, maintains proper cellular function, and restores pro-neuroplastic signaling. In this review, we discuss the anti-AD mechanisms of quercetin and kaempferol and their limitations, and we suggest a potential alternative treatment for AD. Our findings lead us to conclude that a polyherbal kaempferol- and quercetin-rich cocktail could treat AD-related brain damage.

Driving Paediatric Vaccine Recovery in Europe.

BACKGROUND: Childhood vaccination coverage has increased throughout Europe in recent decades. However, challenges persist in many areas within the European Union (EU), resulting in declining coverage rates in many countries in the period between 2010 and 2021. This general trend requires increased efforts to combat barriers around vaccination uptake. Thus, this article aims to summarise key learnings and trends in paediatric vaccination within the EU, with a focus on current challenges and enablers. METHODS: Methodology is based on analysis of primary data, mainly vaccination coverage rates, as well as review and analysis of the select relevant literature, including peer-reviewed articles, academic research papers, official reports, policies, and other publicly available sources. RESULTS: For all vaccines assessed (DTP 1st dose, DTP 3rd dose, Hib3, HepB3, measles 1st dose, measles 2nd dose, and polio 3rd dose), a high degree of variation and fluctuation in coverage can be observed. There is a general trend of declining coverage in 2019 compared to 2010, with lower performing countries, such as Romania and Austria, showing increasingly severe coverage fluctuations between the years examined across the analysed vaccines. CONCLUSIONS: Evidence suggests that increasing both accessibility and information regarding vaccines are key enablers to vaccination uptake. Moreover, given the current challenges the EU is facing, crisis preparedness plans are pertinent to ensure immunity gaps do not further exacerbate the disruption of vaccination systems.

Changing Molecular Profiles of Human Cryptosporidiosis Cases in Scotland as a Result of the Coronavirus Disease, COVID-19 Pandemic.

Cryptosporidium, the most frequently reported parasite in Scotland, causes gastrointestinal illness resulting in diarrhoea, nausea and cramps. Two species are responsible for most cases: Cryptosporidium hominis (C. hominis) and Cryptosporidium parvum (C. parvum). Transmission occurs faecal-orally, through ingestion of contaminated food and water, or direct contact with faeces. In 2020, the COVID-19 pandemic led to global restrictions, including national lockdowns to limit viral transmission. Such interventions led to decreased social mixing, and reduced/no local and international travel, which are factors associated with transmission of multiple communicable diseases, including cryptosporidiosis. This report assessed the impact of the pandemic on Scottish cryptosporidiosis cases, and identified changes in circulating molecular variants of Cryptosporidium species. Molecular data generated using real time PCR and GP60 nested-PCR assays on laboratory-confirmed cryptosporidiosis cases reported during 2018-22 were analysed. The Scottish Microbiology Reference Laboratories (SMiRL), Glasgow, received 774 Cryptosporidium-positive faeces during 2018-22, of which 486 samples were successfully subtyped. During this time period, C. hominis (n = 155; 21%) and C. parvum (n = 572; 77%) were the most commonly detected species. The total number of cases during 2020, which was greatly affected by the pandemic, was markedly lower in comparison to case numbers in the 2 years before and after 2020. The most predominant C. hominis family detected prior to 2020 was the Ib family which shifted to the Ie family during 2022. The most common C. parvum variant during 2018-22 was the IIa family, however a rise in the IId family was observed (n = 6 in 2018 to n = 25 in 2022). The dominant C. hominis subtype IbA10G2, which accounted for 71% of C. hominis subtypes in 2018-19 was superseded by three rare subtypes: IeA11G3T3 (n = 15), IdA16 (n = 8) and IbA9G3 (n = 3) by 2022. Frequently reported C. parvum subtypes in 2018-19 were IIaA15G2R1 and IIaA17G1R1, accounting for 59% of total C. parvum subtypes. By 2022, IIaA15G2R1 remained the most common (n = 28), however three unusual subtypes in Scotland emerged: IIdA24G1 (n = 7), IIaA16G3R1 (n = 7) and IIaA15G1R2 (n = 7). Continuous monitoring of Cryptosporidium variants following the pandemic will be essential to explore further changes and emergence of strains with altered virulence.

Acanthamoeba keratitis: Molecular typing of Acanthamoeba species directly from ocular tissue.

This report explores the molecular profiling of Acanthamoeba spp. from individuals in the UK suffering from a debilitating, sight-threatening disease of the cornea known as Acanthamoeba keratitis (AK). Seventy ocular samples from individuals undergoing investigations for AK were sent to the Scottish Microbiology Reference Laboratories (SMiRL), Glasgow during 2017-2019, and subjected to DNA extraction followed by in-depth molecular typing using a nested PCR/bi-directional sequencing approach. Of the 70 samples tested, 40 were PCR-positive. Of these, 32 were successfully sequenced and assigned to two of 23 existing genotypes termed T1 to T23. Molecular profiling of the 32 samples highlighted two genotypes, namely T3 (n = 3) and T4 (n = 29). For those 29 samples identified as the T4 genotype, a sub-genotype (T4A-T4H) was recorded: T4A (n = 18); T4B (n = 5); T4C (n = 1); T4E (n = 4); and T4F (n = 1). This study highlights that the T4 genotype and T4A subtype are the predominant molecular variants to cause ocular disease in the UK. Gaining in-depth information on the molecular profiling of Acanthamoeba spp. is essential to increase our understanding of the source(s) of infection, transmission pathways, and potential associations with clinical outcomes for this rare, yet potentially debilitating ocular disease.

Examination of race and gender differences in predictors of neuropsychological decline and development of Alzheimer's disease.

ObjectiveBlack adults are diagnosed with Alzheimer's disease (AD) at higher rates than White adults. Biopsychosocial risk factors that differentially affect individuals by race, including health, education, and APOE e4, may explain these findings. Some research suggests that the risk for AD associated with the APOE e4 allele may differ by race. Gender differences in AD have also been identified but remain understudied. We examined race, APOE status, vascular risk factors, education, and the interaction of APOE e4 status and race as predictors of cognitive decline and the development of Alzheimer's disease between genders in a large longitudinal sample of older adults. Methods: Participants (N = 4336) were selected from the National Alzheimer's Coordinating Center's Uniform Data Set who completed measures of verbal fluency, naming, and immediate/delayed story memory across 5 years. Analyses were stratified by gender. Follow up interactions examined statistical significance of differences. Results: APOE e4 by race interactions were largely non-significant and dropped from most models. When controlling for health, education, referral source, and Uniform Data Set form (when applicable), few racial differences in cognitive performance over time emerged. Black participants obtained lower scores than White participants on a majority of baseline measures. Race findings did not differ by gender. Hypertension was more strongly predictive of decline in delayed memory among women. Conclusions: Analyses did not support that APOE e4 differentially affects Black individuals. Hypertension may be a more relevant risk factor among women. Results raise questions regarding the accuracy of baseline scores in predicting decline for Black individuals.

A scoping review of risk factors and transmission routes associated with human giardiasis outbreaks in high-income settings.

The flagellated pathogen Giardia duodenalis is one of the leading causes of parasitic gastrointestinal illness worldwide. In many higher income countries, such as the United Kingdom, the disease is often perceived as being travel-related, likely leading to the under-reporting of sporadic cases and outbreaks. A summary of the literature describing outbreaks and risk factors in higher income countries is necessary to improve our understanding of this pathogen and identify existing knowledge gaps. Initial literature searches were carried out in September 2016 and updated at regular intervals until November 2021, using appropriate search terms in Medline, Embase and PubMed databases. A total of 75 papers met the inclusion criteria, revealing that the consumption of contaminated water and contact with young children of diaper-wearing age were the most common transmission routes leading to outbreaks of giardiasis. Of the ten studies where food was primarily associated with outbreaks, food handlers accounted for eight of these. Another reported transmission route was direct contact with fecal material, which was reported in six studies as the primary transmission route. Travel-associated giardiasis was considered the sole transmission route in two studies, whereas multiple transmission routes contributed to giardiasis outbreaks in eleven studies. The evidence around zoonotic transmission was less clear and hampered by the lack of robust and regularly applied parasite molecular typing techniques. This literature review summarizes the findings of Giardia outbreak investigations and epidemiological studies in high-income countries. Transmission routes are identified and discussed to highlight the associated risk factors. These data also indicate gaps in our current knowledge that include the need for robust, in-depth molecular studies and have underscored the importance of water as a transmission route for Giardia cysts. These future molecular studies will improve our understanding of Giardia epidemiology and transmission pathways in higher income countries to prevent spread of this significantly under-reported pathogen.

Validation of a multilocus genotyping scheme for subtyping Cryptosporidium parvum for epidemiological purposes.

Subtyping Cryptosporidium parvum for outbreak investigations or epidemiological surveillance usually relies on DNA sequence analysis of a gene coding for a 60 KDa glycoprotein (gp60). Although gp60 can be useful for allelic discrimination and to help investigate sources and routes of transmission, the presence of common subtypes and recombination during the parasite's sexual life-cycle demand a multilocus-based method for more discriminatory genotyping. While whole genome sequencing would provide the ultimate approach, it is a time consuming and expensive option for faecal parasites such as Cryptosporidium that occur at low density and are difficult to propagate routinely. In this study, we selected and evaluated a panel of previously identified variable-number tandem-repeat (VNTR) markers, to establish a multilocus genotyping scheme based on fragment sizing, appropriate for inter-laboratory surveillance and outbreak investigations. Seven VNTR markers were validated in vitro and demonstrated typeability of 0.85 and discriminatory power of 0.99. The discriminatory power was much greater than the currently used gp60 sequencing (0.74), which identified 26 subtypes, compared to 100 different MLVA profiles within the same sample set. The assay was robust, with repeatable results and reproducibility across three laboratories demonstrating the scheme was suitable for inter-laboratory comparison of C. parvum subtypes. As the majority of genotypes (79%) were unique among epidemiologically unrelated samples, there was efficiency to infer linkage, and epidemiological concordance was observed in historical outbreaks. We propose that the multilocus variable number of tandem repeats analysis scheme is suitable to assist outbreak investigations.

Molecular characterisation of Giardia duodenalis from human and companion animal sources in the United Kingdom using an improved triosephosphate isomerase molecular marker.

Giardia duodenalis is a protozoan parasite known for its ability to cause gastrointestinal disease in human and non-human mammals. In the UK, the full impact of this parasite has yet to be fully explored, due to the limited testing which has been undertaken in humans and the low-resolution assemblage-typing methods currently available. Rather than being primarily a travel-associated condition, a recent study has highlighted that an endemic Giardia cycle is present in the UK, although the source of human disease is unclear in the majority of cases. This study focussed on the improvement of one of the commonly used assemblage-typing assays, a nested topoisomerase phosphate (tpi) PCR, to increase the amplification success rate across both human and companion animal samples. After comparing published primers to full Giardia reference genomes, this marker protocol was optimised and then deployed to test a substantial number of human (n â€‹= â€‹79) and companion animal (n â€‹= â€‹174) samples to gain an insight into the molecular epidemiology of Giardia in the UK. One assemblage A1 and eleven assemblage A2 genotypes were detected in humans, along with and 25 assemblage B genotypes. Assemblage A1 genotypes, known to be human-infective, were found in three feline and one canine sample, while one feline sample contained assemblage A2. Additionally, four feline samples contained assemblage B, which is recognised as potentially human-infective. This study demonstrates the presence of potentially human-infective Giardia genotypes circulating in the companion animal population, notably with 17.4% (8/46) of feline-derived Giardia strains being potentially zoonotic. Using a modified tpi-based genotyping assay, this work highlights the potential for domestic pets to be involved in the endemic transmission of giardiasis in the UK and underlines the need for appropriate hygiene measures to be observed when interacting with both symptomatic and asymptomatic animals. It also serves to underline the requirement for further studies to assess the zoonotic risk of Giardia associated with companion animals in high-income countries.

Making Bengali Brick Lane: claiming and contesting space in East London.

Based on a recent empirical project on 'the Bengal diaspora', the paper explores the construction and contestation of meanings around the iconic East London street, Brick Lane. Taking the 2006 protests around the film Brick Lane as its starting point, the paper draws on original interviews conducted in 2008 with a range of Bengali community representatives, to examine the narratives of space, community and belonging that emerge around the idea of Brick Lane as the 'cultural heartland' of the British Bangladeshi community. By exploring the representation, production and contestation of 'social space' through everyday practices, the paper engages with and contests the representation of minority ethnic 'communities' in the context of contemporary multicultural London and examines the process of 'claiming' and 'making' space in East London. In so doing, the paper contributes to a critical tradition that challenges essentialising and pathologizing accounts of ethnic communities and racialized spaces, or that places them outside of broader social and historical processes - redolent, for example, in contemporary discussions about 'parallel lives' or 'the clash of civilizations'. By contrast, this paper views social space as made through movement and narration, with a particular emphasis on the social agency of local Bengali inhabitants and the multiple meanings that emerge from within this 'imagined community'. However, rather than simply stressing the unfinished and processual nature of spatial meanings, the paper insists on the historical, embodied and affective dimensions of such meaning making, and a reckoning with the broader social and political landscape within which such meanings take shape. The focus on Brick Lane provides an empirically rich, geographically and historically located lens through which to explore the complex role of ethnicity as a marker of social space and of spatial practices of resistance and identity. By exploring Bengali Brick Lane through its narratives of past, present and future, these stories attest to the symbolic and emotional importance of such spaces, and to their complex imaginings.

Cannabidiol and the corticoraphe circuit in post-traumatic stress disorder.

Post-Traumatic Stress Disorder (PTSD), characterized by re-experiencing, avoidance, negative affect, and impaired memory processing, may develop after traumatic events. PTSD is complicated by impaired plasticity and medial prefrontal cortex (mPFC) activity, hyperactivity of the amygdala, and impaired fear extinction. Cannabidiol (CBD) is a promising candidate for treatment due to its multimodal action that enhances plasticity and calms hyperexcitability. CBD's mechanism in the mPFC of PTSD patients has been explored extensively, but literature on the mechanism in the dorsal raphe nucleus (DRN) is lacking. Following the PRISMA guidelines, we examined current literature regarding CBD in PTSD and overlapping symptomologies to propose a mechanism by which CBD treats PTSD via corticoraphe circuit. Acute CBD inhibits excess 5-HT release from DRN to amygdala and releases anandamide (AEA) onto amygdala inputs. By first reducing amygdala and DRN hyperactivity, CBD begins to ameliorate activity disparity between mPFC and amygdala. Chronic CBD recruits the mPFC, creating harmonious corticoraphe signaling. DRN releases enough 5-HT to ameliorate mPFC hypoactivity, while the mPFC continuously excites DRN 5-HT neurons via glutamate. Meanwhile, AEA regulates corticoraphe activity to stabilize signaling. AEA prevents DRN GABAergic interneurons from inhibiting 5-HT release so the DRN can assist the mPFC in overcoming its hypoactivity. DRN-mediated restoration of mPFC activity underlies CBD's mechanism on fear extinction and learning of stress coping.

The first UK report of a rare Cryptosporidium hominis genetic variant isolated during a complex Scottish swimming pool outbreak.

Cryptosporidium species are responsible for causing the majority of parasite-related gastrointestinal infections in the UK. This report describes an outbreak of 12 laboratory-confirmed cryptosporidiosis cases identified as part of a Scottish swimming pool investigation, with 9 primary and 3 secondary cases occurring over an 8-week period. Molecular speciation was successful for 11/12 cases, which revealed 10 Cryptosporidium hominis cases and 1 Cryptosporidium parvum case. Of the 10 C. hominis cases, further typing identified 7 as being an unusual sub-type, IbA6G3, which is the first description in the UK of this rare variant. The remaining three C. hominis cases were identified as the common IbA10G2 subtype. Following implementation of control measures on two occasions, no further cases were reported. This report highlights the importance of molecular typing to identify and characterize outbreaks, and emphasizes the need to adhere to swimming pool guidance. It also raises awareness of the potential for outbreaks to involve multiple species/sub-types, and emphasizes the importance of strong public health leadership to ensure effective multi-agency investigations and management of outbreaks.

Molecular Epidemiology of Giardia Infections in the Genomic Era.

Giardia duodenalis is a major gastrointestinal parasite of humans and animals across the globe. It is also of interest from an evolutionary perspective as it possesses many features that are unique among the eukaryotes, including its distinctive binucleate cell structure. While genomic analysis of a small number of isolates has provided valuable insights, efforts to understand the epidemiology of the disease and the population biology of the parasite have been limited by the molecular tools currently available. We review these tools and assess the impact of affordable and rapid genome sequencing systems increasingly being deployed in diagnostic settings. While these technologies have direct implications for public and veterinary health, they will also improve our understanding of the unique biology of this fascinating parasite.

A descriptive case of persistent Acanthamoeba keratitis: raising awareness of this complex ocular disease.

BACKGROUND: Acanthamoeba species are ubiquitous free-living organisms found in the environment. They can cause a sight-threatening disease of the cornea termed Acanthamoeba keratitis (AK), often associated with contact-lens wearers. This case review describes a persistent presentation of AK and raises awareness of the challenges faced when diagnosing and managing the disease. It highlights the importance of an accurate and rapid diagnosis to assist patient management and to maximize the potential for a better outcome. CASE PRESENTATION: A 73-year-old female was admitted to hospital due to vision impairment of her left eye. Following a clinical examination, the diagnosis of herpes simplex keratitis (HSK) was reported and treated with antivirals. However, deterioration of her keratitis continued after initial treatment, which prompted an investigation into the possibility of AK. Molecular testing of sequential corneal tissue was performed using a real-time PCR assay alongside further clinical examinations. Acanthamoeba species DNA was isolated from seven out of eight corneal tissues over a 12 month period. Following prolonged drug treatment and two corneal transplants, the individual's symptoms ceased and further molecular testing of corneal tissue was negative. CONCLUSIONS: Acanthamoeba keratitis can be easily misdiagnosed due to the similarities in the clinical presentation to other, much more common ocular pathogens. This case highlights the importance of considering AK in the first-line diagnosis, and raises awareness that an early, accurate and rapid diagnosis is crucial to improve patient outcome.

An update on the incidence of human giardiasis in Scotland, 2011-2018.

BACKGROUND: Giardia duodenalis is one of the most common parasites in the UK to cause diarrhoeal illness. Giardiasis is likely to be significantly under-reported in the UK as laboratory testing is largely based on examining stool samples from individuals with a recent travel history. This results in the majority of locally-acquired cases going undetected. To increase awareness of giardiasis, we describe data gathered from cases reported within Scotland during 2011-2018. METHODS: All of the 21 Scottish National Health Service (NHS) diagnostic microbiology laboratories performed microscopy examination to detect Giardia cysts in stools, from mostly travel-related cases. The exception was one laboratory that implemented an antigen-based enzyme immunoassay in 2015. This resulted in every submitted stool being tested for Giardia. Laboratory-confirmed cases of giardiasis were reported to Health Protection Scotland (HPS) via the Electronic Communication of Surveillance in Scotland (ECOSS) during the eight-year period. Data for calculating the incidence per 100,000 of the population were obtained from the National Records of Scotland mid-2018 population estimates in Scotland. RESULTS: A total of 1631 Scottish cases were reported during 2011-2018 (8-year mean: 204; range: 166-269). National Health Service Grampian, Borders and Lothian reported the highest incidence of Giardia (9.8, 7.5 and 6.7 per 100,000, respectively), all of which were above the Scottish mean incidence (3.8 per 100,000). Following the implementation of antigen testing in NHS Grampian during 2015, reports significantly increased 3.6-fold (P = 0.005). The highest incidence of giardiasis occurred in the 20-49 years age group (mean 5.4 per 100,000). Of interest, the mean incidence of giardiasis was significantly higher in males than in females (4.8 versus 3.1 per 100,000, respectively; P < 0.0001). CONCLUSIONS: This report highlights the need to capture enhanced information on every laboratory-confirmed case of giardiasis to gain a better understanding of the local sources and transmission pathways occurring in Scotland. In addition, implementing sensitive, automated technologies across UK NHS diagnostic microbiology laboratories to permit the efficient, routine testing of every submitted stool for Giardia, should be encouraged to ensure all cases are identified and treated appropriately.

PTEN loss promotes rasHa-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via PTEN-associated pathways.

PTEN tumor suppressor gene failure in ras(Ha)-activated skin carcinogenesis was investigated by mating exon 5 floxed-PTEN (Delta5PTEN) mice to HK1.ras mice that expressed a RU486-inducible cre recombinase (K14.creP). PTEN inactivation in K14.cre/PTEN(flx/flx) keratinocytes resulted in epidermal hyperplasia/hyperkeratosis and novel 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas, whereas HK1.ras/K14.cre/PTEN(flx/flx) cohorts displayed a rapid onset of papillomatogenesis due to a synergism of increased AKT activity and extracellular signal-regulated kinase (ERK) elevation. High 5-bromo-4-deoxyuridine labeling in Delta5PTEN papillomas showed that a second promotion mechanism centered on failures in cell cycle control. Elevated cyclin D1 was associated with both HK1.ras/ERK- and Delta5PTEN-mediated AKT signaling, whereas cyclin E2 overexpression seemed dependent on PTEN loss. Spontaneous HK1.ras/Delta5PTEN malignant conversion was rare, whereas TPA promotion resulted in conversion with high frequency. On comparison with all previous HK1.ras carcinomas, such TPA-induced carcinomas expressed atypical retention of keratin K1 and lack of K13, a unique marker profile exhibited by TPA-induced K14.cre/PTEN(flx/flx) papillomas that also lacked endogenous c-ras(Ha) activation. Moreover, in all PTEN-null tumors, levels of ras(Ha)-associated total ERK protein became reduced, whereas phosphorylated ERK and cyclin D1 were lowered in late-stage papillomas returning to elevated levels, alongside increased cyclin E2 expression, in TPA-derived carcinomas. Thus, during early papillomatogenesis, PTEN loss promotes ras(Ha) initiation via elevation of AKT activity and synergistic failures in cyclin regulation. However, in progression, reduced ras(Ha)-associated ERK protein and activity, increased Delta5PTEN-associated cyclin E2 expression, and unique K1/K13 profiles following TPA treatment suggest that PTEN loss, rather than ras(Ha) activation, gives rise to a population of cells with greater malignant potential.