An approach to teaching psychiatry to medical students in the time of Covid-19.

In this time of Covid-19, life in healthcare has changed immeasurably. It has rapidly been injected with an 'all hands-on deck' approach, to facilitate the necessary adaptations required to reduce the spread of the virus and deliver frontline clinical care. Inevitably aspects of these changes have disrupted the delivery of medical education, notably clinical placements have been cancelled and social distancing guidelines prohibit face-to-face teaching. The training of future doctors is an essential part of this effort. Indeed, the emergence of a global health threat has underlined its continued importance. For medical educators and students alike, we have been presented with a challenge. Concurrently, this presents us with an impetus and opportunity for innovation. For some time now, a transformation in medical education has been called for, with an increasing recognition of the need to prepare students for the changing landscape of healthcare systems. This has included a focus on the use of technology-enhanced and self-directed learning. As a team of educators and clinicians in psychiatry, working in the School of Medicine and Medical Sciences (SMMS) in University College Dublin (UCD), we will share how we have responded. We outline the adaptations made to our 'Psychiatry' module and consider the influence this may have on its future delivery. These changes were informed by direct student input.

Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data

Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. Methods In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. Findings 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 434 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27­0·37]) and 82% at 8 weeks (0·18 [0·14­0·23]) following the week in which significant changes in population movements were recorded. Interpretation The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Funding Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).

Changing prescribing patterns in an Irish community mental health service.

OBJECTIVES: Medication is an important component of the treatment of many mental illnesses. Very little information is available about the particular medications that are being prescribed by community mental health services and how this has changed over time. We set out to obtain details of psychiatric medications being prescribed by one Irish community mental health service. METHOD: All prescribing by the Cluain Mhuire Community Mental Health Service became electronic during 2004. Using Business Intelligence software, we obtained details of all psychiatric medications prescribed from 2005 to 2016. We compared numbers of prescriptions written in the first 6 years (2005-2010) with the following 6 (2011-2016). RESULTS: Olanzapine was the most commonly prescribed medication throughout but its use declined by one-quarter over the study period. Clozapine, quetiapine, aripiprazole and haloperidol prescribing increased. Prescriptions for mood stabilisers and antidepressants fell by 25%. Sedative prescriptions declined by almost 50%. Absolute numbers of prescriptions written for methylphenidate and pregabalin were small but increased dramatically over the time period. CONCLUSIONS: This community mental health service prescribed less of most psychiatric medications in 2016, than had been the case in 2005. This is despite an increase in the numbers of patients seen over the same period. It is not clear if this pattern is echoed in other services.

Identifying latent tuberculosis in high-risk populations: systematic review and meta-analysis of test accuracy.

BACKGROUND: The relative accuracy of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) in identifying latent tuberculosis infection (LTBI) is uncertain.OBJECTIVE: To perform a systematic review and meta-analysis to compare the sensitivity and specificity of IGRAs and TST for the prediction of progression to clinical tuberculosis (TB).METHODS: We searched electronic databases (e.g., MEDLINE and EMBASE) from December 2009 to September 2018 for prospective studies that followed up individuals who had undergone testing with commercial IGRAs and/or TST but had not received treatment based on the test result. The sensitivity and specificity estimates were pooled using a Bayesian bivariate random-effects model.RESULTS: Twenty-five studies, mostly with moderate to high risk of bias and a mean follow-up time ranging from 1 to 5 years were included. TST (10-15 mm) tended to have lower sensitivity and higher specificity than QuantiFERON® Gold In-Tube, T-SPOT®.TB and TST (5 mm). The evidence did not indicate that any test outperformed the others due to wide and overlapping 95% credible intervals.CONCLUSION: The evidence following individuals who had undergone testing for LTBI and had progressed to clinical TB is sparse. We did not find that IGRAs were superior to TST or vice versa; however, as our findings are based on a small number of studies with methodological limitations and great uncertainty around the pooled estimates, the results should be interpreted with caution.

Analysis of individual patient data to describe the incubation period distribution of Shiga-toxin producing Escherichia coli.

Shiga-toxin producing Escherichia coli (STEC) is a pathogen that can cause bloody diarrhoea and severe complications. Cases occur sporadically but outbreaks are also common. Understanding the incubation period distribution and factors influencing it will help in the investigation of exposures and consequent disease control. We extracted individual patient data for STEC cases associated with outbreaks with a known source of exposure in England and Wales. The incubation period was derived and cases were described according to patient and outbreak characteristics. We tested for heterogeneity in reported incubation period between outbreaks and described the pattern of heterogeneity. We employed a multi-level regression model to examine the relationship between patient characteristics such as age, gender and reported symptoms; and outbreak characteristics such as mode of transmission with the incubation period. A total of 205 cases from 41 outbreaks were included in the study, of which 64 cases (31%) were from a single outbreak. The median incubation period was 4 days. Cases reporting bloody diarrhoea reported shorter incubation periods compared with cases without bloody diarrhoea, and likewise, cases aged between 40 and 59 years reported shorter incubation period compared with other age groups. It is recommended that public health officials consider the characteristics of cases involved in an outbreak in order to inform the outbreak investigation and the period of exposure to be investigated.

Are food exposures obtained through commercial market panels representative of the general population? Implications for outbreak investigations.

Current methods of control recruitment for case-control studies can be slow (a particular issue for outbreak investigations), resource-intensive and subject to a range of biases. Commercial market panels are a potential source of rapidly recruited controls. Our study evaluated food exposure data from these panel controls, compared with an established reference dataset. Market panel data were collected from two companies using retrospective internet-based surveys; these were compared with reference data from the National Diet and Nutrition Survey (NDNS). We used logistic regression to calculate adjusted odds ratios to compare exposure to each of the 71 food items between the market panel and NDNS participants. We compared 2103 panel controls with 2696 reference participants. Adjusted for socio-demographic factors, exposure to 90% of foods was statistically different between both panels and the reference data. However, these differences were likely to be of limited practical importance for 89% of Panel A foods and 79% of Panel B foods. Market panel food exposures were comparable with reference data for common food exposures but more likely to be different for uncommon exposures. This approach should be considered for outbreak investigation, in conjunction with other considerations such as population at risk, timeliness of response and study resources.

The impact and indications for Oncotype DX on adjuvant treatment recommendations when third-party funding is unavailable.

OBJECTIVES: Industry-supported decision impact studies demonstrate that Oncotype Dx (ODX) changes treatment recommendations (TR) in 24-40% of hormone receptor+/HER2- patients. ODX is not reimbursed by third-party payers in Australia, potentially resulting in more selective use. We sought to evaluate the impact of self-funded ODX on TRs. METHODS: Data collected included demographics, tumor characteristics, indication for ODX and pre- and post-recurrence score (RS) TR. Primary endpoint was frequency of TR change and associations with TR change were sought. RESULTS: Eighteen physicians contributed 382 patients (median age 54). A total of 232 (61%) of tumors were T1 and were grade 1, 2 and 3 in 49 (13%), 252 (66%) and 79 (21%). A total of 257 (67%) were node negative. Assay indications were: confirm need for chemotherapy (CT) (36%), confirm omission of CT (40%) and genuine equipoise (24%). RS was low (≤17) in 55%, intermediate (18-31) in 36% and high (≥32) in 9%. Thirty-eight percent of patients had TR change post-ODX. Sixty-five percent of patients recommended CT pre-ODX changed to hormone therapy alone (HT)-more likely if lower grade and if ER and/or PR > 10%. Fourteen percent of patients with pre-ODX TR for HT added CT-more likely if ER and/or PR ≤10% and if Ki67 > 15% Overall, TR for CT decreased from 47% to 24%. CONCLUSION: Patient-funded ODX changed TRs in 38% of patients, de-escalating 65% from CT to HT and adding CT to 14% of those recommended HT. These changes were greater than an industry-funded study suggesting that physicians can identify situations where the assay may influence decisions.

Use of gender distribution in routine surveillance data to detect potential transmission of gastrointestinal infections among men who have sex with men in England.

Detecting gastrointestinal (GI) infection transmission among men who have sex with men (MSM) in England is complicated by a lack of routine sexual behavioural data. We investigated whether gender distributions might generate signals for increased transmission of GI pathogens among MSM. We examined the percentage male of laboratory-confirmed patient-episodes for patients with no known travel history for 10 GI infections of public health interest in England between 2003 and 2013, stratified by age and region. An adult male excess was observed for Shigella spp. (annual maximum 71% male); most pronounced for those aged 25-49 years and living in London, Brighton and Manchester. An adult male excess was observed every year for Entamoeba histolytica (range 59.8-76.1% male), Giardia (53.1-57.6%) and Campylobacter (52.1-53.5%) and for a minority of years for hepatitis A (max. 69.8%) and typhoidal salmonella (max. 65.7%). This approach generated a signal for excess male episodes for six GI pathogens, including a characterised outbreak of Shigella among MSM. Stratified analyses by geography and age group were consistent with MSM transmission for Shigella. Optimisation and routine application of this technique by public health authorities elsewhere might help identify potential GI infection outbreaks due to sexual transmission among MSM, for further investigation.

Online market research panel members as controls in case-control studies to investigate gastrointestinal disease outbreaks: early experiences and lessons learnt from the UK.

Established methods of recruiting population controls for case-control studies to investigate gastrointestinal disease outbreaks can be time consuming, resulting in delays in identifying the source or vehicle of infection. After an initial evaluation of using online market research panel members as controls in a case-control study to investigate a Salmonella outbreak in 2013, this method was applied in four further studies in the UK between 2014 and 2016. We used data from all five studies and interviews with members of each outbreak control team and market research panel provider to review operational issues, evaluate risk of bias in this approach and consider methods to reduce confounding and bias. The investigators of each outbreak reported likely time and cost savings from using market research controls. There were systematic differences between case and control groups in some studies but no evidence that conclusions on the likely source or vehicle of infection were incorrect. Potential selection biases introduced by using this sampling frame and the low response rate are unclear. Methods that might reduce confounding and some bias should be balanced with concerns for overmatching. Further evaluation of this approach using comparisons with traditional methods and population-based exposure survey data is recommended.

An evaluation of health protection practices for the investigation and management of Cryptosporidium in England and Wales.

Background: Cryptosporidium is a major cause of gastroenteritis (cryptosporidiosis). Case and outbreak report rates vary geographically, which may in part reflect public health practice. Methods: To examine the public health management of cryptosporidiosis, an online questionnaire was administered to the 28 Health Protection Teams (HPTs) in England and Wales in 2014. Practices for investigation and management of cases and outbreaks were compared. Results: Practice varied among the 24 (86%) respondents in terms of who undertook actions (HPT or Local Authority) to investigate and manage cryptosporidiosis. HPTs without exceedance monitoring detected fewer outbreaks (1/5, 20%) than those with it (13/19, 68%) (P = 0.12), and those that always administered a risk-factor questionnaire detected more outbreaks (12/19, 63%) than those who did this only sometimes (2/5, 40%) (P = 0.62). Significantly more HPTs with a system to detect common exposures reported at least one outbreak (14/19, 74%) compared to HPTs with no system (0/5) (P = 0.01). Conclusions: Applying exceedance monitoring, using a standardized questionnaire taking into account the incubation period for Cryptosporidium, and having a structured system to detect common exposures increased outbreak detection. Information about all cases should be shared between local public health authorities, and current guidance used for the prevention of spread.

A systematic review and meta-analysis on the incubation period of Campylobacteriosis.

Accurate knowledge of pathogen incubation period is essential to inform public health policies and implement interventions that contribute to the reduction of burden of disease. The incubation period distribution of campylobacteriosis is currently unknown with several sources reporting different times. Variation in the distribution could be expected due to host, transmission vehicle, and organism characteristics, however, the extent of this variation and influencing factors are unclear. The authors have undertaken a systematic review of published literature of outbreak studies with well-defined point source exposures and human experimental studies to estimate the distribution of incubation period and also identify and explain the variation in the distribution between studies. We tested for heterogeneity using I 2 and Kolmogorov-Smirnov tests, regressed incubation period against possible explanatory factors, and used hierarchical clustering analysis to define subgroups of studies without evidence of heterogeneity. The mean incubation period of subgroups ranged from 2·5 to 4·3 days. We observed variation in the distribution of incubation period between studies that was not due to chance. A significant association between the mean incubation period and age distribution was observed with outbreaks involving only children reporting an incubation of 1·29 days longer when compared with outbreaks involving other age groups.

A seroprevalence study to determine the frequency of hantavirus infection in people exposed to wild and pet fancy rats in England.

Recent cases of acute kidney injury due to Seoul hantavirus infection from exposure to wild or pet fancy rats suggest this infection is increasing in prevalence in the UK. We conducted a seroprevalence study in England to estimate cumulative exposure in at-risk groups with contact with domesticated and wild rats to assess risk and inform public health advice. From October 2013 to June 2014, 844 individual blood samples were collected. Hantavirus seroprevalence amongst the pet fancy rat owner group was 34.1% (95% CI 23·9-45·7%) compared with 3·3% (95% CI 1·6-6·0) in a baseline control group, 2·4% in those with occupational exposure to pet fancy rats (95% CI 0·6-5·9) and 1·7% with occupational exposure to wild rats (95% CI 0·2-5·9). Variation in seroprevalence across groups with different exposure suggests that occupational exposure to pet and wild rats carries a very low risk, if any. However incidence of hantavirus infection among pet fancy rat owners/breeders, whether asymptomatic, undiagnosed mild viral illness or more severe disease may be very common and public health advice needs to be targeted to this at-risk group.

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease.

Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNß in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNß selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNß in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.

Genetic Diversity of Campylobacter jejuni and Campylobacter coli Isolates from Conventional Broiler Flocks and the Impacts of Sampling Strategy and Laboratory Method.

The genetic diversity of Campylobacter jejuni and Campylobacter coliisolates from commercial broiler farms was examined by multilocus sequence typing (MLST), with an assessment of the impact of the sample type and laboratory method on the genotypes of Campylobacter isolated. A total of 645C. jejuniand 106C. coli isolates were obtained from 32 flocks and 17 farms, with 47 sequence types (STs) identified. The Campylobacter jejuniisolates obtained by different sampling approaches and laboratory methods were very similar, with the same STs identified at similar frequencies, and had no major effect on the genetic profile of Campylobacter population in broiler flocks at the farm level. ForC. coli, the results were more equivocal. While some STs were widely distributed within and among farms and flocks, analysis of molecular variance (AMOVA) revealed a high degree of genetic diversity among farms forC. jejuni, where farm effects accounted for 70.5% of variance, and among flocks from the same farm (9.9% of variance for C. jejuni and 64.1% forC. coli). These results show the complexity of the population structure of Campylobacterin broiler production and that commercial broiler farms provide an ecological niche for a wide diversity of genotypes. The genetic diversity of C. jejuni isolates among broiler farms should be taken into account when designing studies to understand Campylobacter populations in broiler production and the impact of interventions. We provide evidence that supports synthesis of studies on C. jejuni populations even when laboratory and sampling methods are not identical.

A Medium-Throughput Single Cell CRISPR-Cas9 Assay to Assess Gene Essentiality.

BACKGROUND: Target selection for oncology is a crucial step in the successful development of therapeutics. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of specific loci offers an alternative method to RNA interference and small molecule inhibitors for determining whether a cell line is dependent on a specific gene product for proliferation or survival. In our initial studies using CRISPR-Cas9 to verify the dependence on EZH2 activity for proliferation of a SMARCB1/SNF5/INI1 mutant malignant rhabdoid tumor (MRT) cell line, we noted that the initial reduction in proliferation was lost over time. We hypothesized that in the few cells that retain proliferative capacity, at least one allele of EZH2 remains functional. To verify this, we developed an assay to analyze 10s-100s of clonal cell populations for target gene disruption using restriction digest and fluorescent fragment length analyses. RESULTS: Our results clearly show that in cell lines in which EZH2 is essential for proliferation, at least one potentially functional allele of EZH2 is retained in the clones that survive. CONCLUSION: This assay clearly indicates whether or not a specific gene is essential for survival and/or proliferation in a given cell line. Such data can aid the development of more robust therapeutics by increasing confidence in target selection.

Immunogenicity of a low-dose diphtheria, tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard-dose diphtheria, tetanus, acellular pertussis when used as a pre-school booster in UK children: A 5-year follow-up of a randomised controlled study.

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap-IPV, Repevax(®); Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis(®); Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap-IPV, Tetravac(®); Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection. All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap-IPV, Tdap+OPV and DTap-IPV, respectively, had protective antitoxin levels greater than 0.1IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV. Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination.