Puppy Socialisation Experiences in Relation to Age and COVID-19 Lockdown Restrictions in the UK and ROI.

Limited socialisation can contribute to the development of undesirable dog behaviours. The COVID-19 lockdown potentially limited socialisation opportunities, which may negatively impact the future behaviour of puppies raised during lockdown. Data were gathered from longitudinal study participants in the United Kingdom/Republic of Ireland via multiple questionnaires between May 2016 and November 2022. The impact of age and lockdown phase (pre-, during, and post-) on the types of socialisation experiences of 8-to-19-week-old puppies and the recency of socialisation experiences of approximately 6-month-old puppies were examined. Puppies under 19-weeks had significantly more types of socialisation experiences (from a predefined list) as they aged, and pre-lockdown compared to post-lockdown, but not between other lockdown phases. Most 6-month-old puppies had met a new adult or dog outside the household, a familiar dog, and/or a child within the last 1-7 days, and this was similar between lockdown phases. During lockdown, 6-month-old puppies experienced longer periods between meeting a new adult in their home. Puppies were hypothesised to have had fewer experiences during lockdown, but this was not found. However, the quantity and quality of these experiences may have been affected. Future research within this longitudinal study will explore relationships between the timing and type of experiences had by puppies and their subsequent behaviour.

Antimicrobial resistance prevalence in bloodstream infection in 29 European countries by age and sex: An observational study.

BACKGROUND: Antibiotic usage, contact with high transmission healthcare settings as well as changes in immune system function all vary by a patient's age and sex. Yet, most analyses of antimicrobial resistance (AMR) ignore demographic indicators and provide only country-level resistance prevalence values. This study aimed to address this knowledge gap by quantifying how resistance prevalence and incidence of bloodstream infection (BSI) varied by age and sex across bacteria and antibiotics in Europe. METHODS AND FINDINGS: We used patient-level data collected as part of routine surveillance between 2015 and 2019 on BSIs in 29 European countries from the European Antimicrobial Resistance Surveillance Network (EARS-Net). A total of 6,862,577 susceptibility results from isolates with age, sex, and spatial information from 944,520 individuals were used to characterise resistance prevalence patterns for 38 different bacterial species and antibiotic combinations, and 47% of these susceptibility results were from females, with a similar age distribution in both sexes (mean of 66 years old). A total of 349,448 isolates from 2019 with age and sex metadata were used to calculate incidence. We fit Bayesian multilevel regression models by country, laboratory code, sex, age, and year of sample to quantify resistant prevalence and provide estimates of country-, bacteria-, and drug-family effect variation. We explore our results in greater depths for 2 of the most clinically important bacteria-antibiotic combinations (aminopenicillin resistance in Escherichia coli and methicillin resistance in Staphylococcus aureus) and present a simplifying indicative index of the difference in predicted resistance between old (aged 100) and young (aged 1). At the European level, we find distinct patterns in resistance prevalence by age. Trends often vary more within an antibiotic family, such as fluroquinolones, than within a bacterial species, such as Pseudomonas aeruginosa. Clear resistance increases by age for methicillin-resistant Staphylococcus aureus (MRSA) contrast with a peak in resistance to several antibiotics at approximately 30 years of age for P. aeruginosa. For most bacterial species, there was a u-shaped pattern of infection incidence with age, which was higher in males. An important exception was E. coli, for which there was an elevated incidence in females between the ages of 15 and 40. At the country-level, subnational differences account for a large amount of resistance variation (approximately 38%), and there are a range of functional forms for the associations between age and resistance prevalence. For MRSA, age trends were mostly positive, with 72% (n = 21) of countries seeing an increased resistance between males aged 1 and 100 years and a greater change in resistance in males. This compares to age trends for aminopenicillin resistance in E. coli which were mostly negative (males: 93% (n = 27) of countries see decreased resistance between those aged 1 and 100 years) with a smaller change in resistance in females. A change in resistance prevalence between those aged 1 and 100 years ranged up to 0.51 (median, 95% quantile of model simulated prevalence using posterior parameter ranges 0.48, 0.55 in males) for MRSA in one country but varied between 0.16 (95% quantile 0.12, 0.21 in females) to -0.27 (95% quantile -0.4, -0.15 in males) across individual countries for aminopenicillin resistance in E. coli. Limitations include potential bias due to the nature of routine surveillance and dependency of results on model structure. CONCLUSIONS: In this study, we found that the prevalence of resistance in BSIs in Europe varies substantially by bacteria and antibiotic over the age and sex of the patient shedding new light on gaps in our understanding of AMR epidemiology. Future work is needed to determine the drivers of these associations in order to more effectively target transmission and antibiotic stewardship interventions.

Owner expectations and surprises of dog ownership experiences in the United Kingdom.

Introduction: Although many owners are satisfied by dog ownership, large numbers of dogs are relinquished annually, with an estimated 130,000 dogs cared for each year by rescue organisations in the UK. Unrealistic ownership expectations are a potential factor in the decision to relinquish and therefore understanding what surprises owners about the realities of ownership and how this meets their expectations is vital. Methods: Using a retrospective cross-sectional cohort study design, as part of Dogs Trust's National Dog Survey 2021, owners were asked 'what has surprised you most about owning a dog?' and to classify how their experiences had compared with their expectations on a list of aspects of ownership as either more than, less than or as expected. Free text responses (n= 2,000) were analysed using reflexive thematic analysis in NVivo Pro (v.12 QSR) and a quantitative summary of classified expectations (n=354,224) was conducted in R. Results: Many aspects of ownership were reported to be as expected, however a discrepancy between expectation and reality regarding some aspects was revealed. The cost of vet visits was greater than expected for the majority of respondents (52%), whilst other factors that often exceeded expectations included buying/rehoming cost (33%) and amount of patience needed (25%). Damage to furniture was less than expected for many (50%) as was damage to garden (33%). From the thematic analysis, four themes were generated that reflected what surprised owners most about ownership: emotional connectedness of human-dog relationships; dog's impact on human health/wellbeing; understanding what dogs are like; and meeting the demands of ownership. Conclusion: Overall these results aid our understanding of dog-human interactions, highlighting the complexity of the dog-owner relationship which may come with unanticipated costs. Whilst this study's results are reassuring given many aspects of ownership were as expected, and surprises were often positive, some areas had greater impacts than expected, raising opportunities for intervention, resources or support. The aim would be to manage owners' expectations prior to acquisition or ensure these are more realistically met, reducing the likelihood of negative welfare implications for both dog and owner.

Individualised, short-course antibiotic treatment versus usual long-course treatment for ventilator-associated pneumonia (REGARD-VAP): a multicentre, individually randomised, open-label, non-inferiority trial.

BACKGROUND: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged hospitalisation, excessive antibiotic use and, consequently, increased antimicrobial resistance. In this phase 4, randomised trial, we aimed to establish whether a pragmatic, individualised, short-course antibiotic treatment strategy for VAP was non-inferior to usual care. METHODS: We did an individually randomised, open-label, hierarchical non-inferiority-superiority trial in 39 intensive care units in six hospitals in Nepal, Singapore, and Thailand. We enrolled adults (age ≥18 years) who met the US Centers for Disease Control and Prevention National Healthcare Safety Network criteria for VAP, had been mechanically ventilated for 48 h or longer, and were administered culture-directed antibiotics. In culture-negative cases, empirical antibiotic choices were made depending on local hospital antibiograms reported by the respective microbiology laboratories or prevailing local guidelines. Participants were assessed until fever resolution for 48 h and haemodynamic stability, then randomly assigned (1:1) to individualised short-course treatment (≤7 days and as short as 3-5 days) or usual care (≥8 days, with precise durations determined by the primary clinicians) via permuted blocks of variable sizes (8, 10, and 12), stratified by study site. Independent assessors for recurrent pneumonia and participants were masked to treatment allocation, but clinicians were not. The primary outcome was a 60-day composite endpoint of death or pneumonia recurrence. The non-inferiority margin was prespecified at 12% and had to be met by analyses based on both intention-to-treat (all study participants who were randomised) and per-protocol populations (all randomised study participants who fulfilled the eligibility criteria, met fitness criteria for antibiotic discontinuation, and who received antibiotics for the duration specified by their allocation group). This study is registered with ClinicalTrials.gov, number NCT03382548. FINDINGS: Between May 25, 2018, and Dec 16, 2022, 461 patients were enrolled and randomly assigned to the short-course treatment group (n=232) or the usual care group (n=229). Median age was 64 years (IQR 51-74) and 181 (39%) participants were female. 460 were included in the intention-to-treat analysis after excluding one withdrawal (231 in the short-course group and 229 in the usual care group); 435 participants received the allocated treatment and fulfilled eligibility criteria, and were included in the per-protocol population. Median antibiotic treatment duration for the index episodes of VAP was 6 days (IQR 5-7) in the short-course group and 14 days (10-21) in the usual care group. 95 (41%) of 231 participants in the short-course group met the primary outcome, compared with 100 (44%) of 229 in the usual care group (risk difference -3% [one-sided 95% CI -∞ to 5%]). Results were similar in the per-protocol population. Non-inferiority of short-course antibiotic treatment was met in the analyses, although superiority compared with usual care was not established. In the per-protocol population, antibiotic side-effects occurred in 86 (38%) of 224 in the usual care group and 17 (8%) of 211 in the short-course group (risk difference -31% [95% CI -37 to -25%; p<0·0001]). INTERPRETATION: In this study of adults with VAP, individualised shortened antibiotic duration guided by clinical response was non-inferior to longer treatment durations in terms of 60-day mortality and pneumonia recurrence, and associated with substantially reduced antibiotic use and side-effects. Individualised, short-course antibiotic treatment for VAP could help to reduce the burden of side-effects and the risk of antibiotic resistance in high-resource and resource-limited settings. FUNDING: UK Medical Research Council; Singapore National Medical Research Council. TRANSLATIONS: For the Thai and Nepali translations of the abstract see Supplementary Materials section.

Motile Living Biobots Self-Construct from Adult Human Somatic Progenitor Seed Cells.

Fundamental knowledge gaps exist about the plasticity of cells from adult soma and the potential diversity of body shape and behavior in living constructs derived from genetically wild-type cells. Here anthrobots are introduced, a spheroid-shaped multicellular biological robot (biobot) platform with diameters ranging from 30 to 500 microns and cilia-powered locomotive abilities. Each Anthrobot begins as a single cell, derived from the adult human lung, and self-constructs into a multicellular motile biobot after being cultured in extra cellular matrix for 2 weeks and transferred into a minimally viscous habitat. Anthrobots exhibit diverse behaviors with motility patterns ranging from tight loops to straight lines and speeds ranging from 5-50 microns s-1 . The anatomical investigations reveal that this behavioral diversity is significantly correlated with their morphological diversity. Anthrobots can assume morphologies with fully polarized or wholly ciliated bodies and spherical or ellipsoidal shapes, each related to a distinct movement type. Anthrobots are found to be capable of traversing, and inducing rapid repair of scratches in, cultured human neural cell sheets in vitro. By controlling microenvironmental cues in bulk, novel structures, with new and unexpected behavior and biomedically-relevant capabilities, can be discovered in morphogenetic processes without direct genetic editing or manual sculpting.

A systematic review of neglected tropical diseases (NTDs) in Myanmar.

BACKGROUND: Neglected tropical diseases (NTDs) affect most impoverished communities in developing countries, like Myanmar in Southeast Asia. NTDs have been understudied and underreported in Myanmar. METHODS: A systematic review of published and grey literature (1900-2023) on neglected tropical diseases (NTDs) in Myanmar was conducted. The literature search included five international databases: PubMed, EMBASE, Ovid Global Health, and Web of Science Core Collection and one national database: the Myanmar Central Biomedical Library (locally published papers and grey literature). The selection criteria included articles with all types of study designs of current or previous infections conducted in humans, that reported NTDs, recognised by WHO, US CDC, and listed in PLoS NTDs. We included melioidosis and rickettsioses which we consider also meet the definition of an NTD. RESULTS: A total of 5941 records were retrieved and screened, of which, 672 (11%) met the selection criteria and were included in this review. Of the included articles, 449 (65%) were published after 2000 and 369 (55%) were from two regions (Yangon and Mandalay) of Myanmar. Of the included articles, 238 (35%) reported bacterial NTDs, 212 (32%) viral NTDs, 153 (23%) helminth NTDs, 25 (4%) protozoal NTDs and 39 (6%) reported more than one aetiology. Based on reported frequency in descending order, the bacterial NTDs were leprosy, Escherichia coli enteritis, salmonellosis, cholera, shigellosis, melioidosis, leptospirosis and rickettsioses; the viral NTDs were dengue, chikungunya and Japanese encephalitis virus (JEV) infection; the protozoal NTDs were amoebiasis, giardiasis and leishmaniasis, and the helminth NTDs were ascariasis, trichuriasis, hookworm disease, filariasis and strongyloidiasis. CONCLUSION: This review summarises NTDs reported in Myanmar over the past 100 years. The findings suggest that most NTDs are likely to be under reported, especially from the majority of the country which is far from academic centres. Research capacity building together with strengthening of laboratory systems would lead to better understanding of the true burden of NTDs in Myanmar. TRIAL REGISTRATION: PROSPERO registration ID: CRD42018092627.

The uncertain role of substandard and falsified medicines in the emergence and spread of antimicrobial resistance.

Approximately 10% of antimicrobials used by humans in low- and middle-income countries are estimated to be substandard or falsified. In addition to their negative impact on morbidity and mortality, they may also be important drivers of antimicrobial resistance. Despite such concerns, our understanding of this relationship remains rudimentary. Substandard and falsified medicines have the potential to either increase or decrease levels of resistance, and here we discuss a range of mechanisms that could drive these changes. Understanding these effects and their relative importance will require an improved understanding of how different drug exposures affect the emergence and spread of resistance and of how the percentage of active pharmaceutical ingredients in substandard and falsified medicines is temporally and spatially distributed.

The burden and dynamics of hospital-acquired SARS-CoV-2 in England.

Hospital-based transmission had a dominant role in Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) epidemics1,2, but large-scale studies of its role in the SARS-CoV-2 pandemic are lacking. Such transmission risks spreading the virus to the most vulnerable individuals and can have wider-scale impacts through hospital-community interactions. Using data from acute hospitals in England, we quantify within-hospital transmission, evaluate likely pathways of spread and factors associated with heightened transmission risk, and explore the wider dynamical consequences. We estimate that between June 2020 and March 2021 between 95,000 and 167,000 inpatients acquired SARS-CoV-2 in hospitals (1% to 2% of all hospital admissions in this period). Analysis of time series data provided evidence that patients who themselves acquired SARS-CoV-2 infection in hospital were the main sources of transmission to other patients. Increased transmission to inpatients was associated with hospitals having fewer single rooms and lower heated volume per bed. Moreover, we show that reducing hospital transmission could substantially enhance the efficiency of punctuated lockdown measures in suppressing community transmission. These findings reveal the previously unrecognized scale of hospital transmission, have direct implications for targeting of hospital control measures and highlight the need to design hospitals better equipped to limit the transmission of future high-consequence pathogens.

Intracranial Empyemas in the COVID-19 Era: A New Phenomenon? A Paediatric Case Series and Review of the Literature.

INTRODUCTION: We present the largest series of paediatric intracranial empyemas occurring after COVID-19 infection to date, and discuss the potential implications of the pandemic on this neurosurgical pathology. METHODS: Patients admitted to our centre between January 2016 and December 2021 with a confirmed radiological diagnosis of intracranial empyema were retrospectively reviewed, excluding non-otorhinological source cases. Patients were grouped according to onset before or after onset of the COVID-19 pandemic and COVID-19 status. A literature review of all post-COVID-19 intracranial empyemas was performed. SPSS v27 was used for statistical analysis. RESULTS: Sixteen patients were diagnosed with intracranial empyema: n = 5 prior to 2020 and n = 11 after, resulting in an average annual incidence of 0.3% prior to onset of the pandemic and 1.2% thereafter. Of those diagnosed since the pandemic, 4 (25%) were confirmed to have COVID-19 on recent PCR test. Time from COVID-19 infection until empyema diagnosis ranged from 15 days to 8 weeks. Mean age for post-COVID-19 cases was 8.5 years (range: 7-10 years) compared to 11 years in non-COVID cases (range: 3-14 years). Streptococcus intermedius was grown in all cases of post-COVID-19 empyema, and 3 of 4 (75%) post-COVID-19 cases developed cerebral sinus thromboses, compared to 3 of 12 (25%) non-COVID-19 cases. All cases were discharged home with no residual deficit. CONCLUSION: Our post-COVID-19 intracranial empyema series demonstrates a greater proportion of cerebral sinus thromboses than non-COVID-19 cases, potentially reflecting the thrombogenic effects of COVID-19. Incidence of intracranial empyema at our centre has increased since the start of the pandemic, causes of which require further investigation and multicentre collaboration.

Unpredictability of maternal environment shapes offspring behaviour without affecting stress-induced cortisol in an annual vertebrate.

Exposure of females to stressful conditions during pregnancy or oogenesis has a profound effect on the phenotype of their offspring. For example, offspring behavioural phenotype may show altered patterns in terms of the consistency of behavioural patterns and their average level of performance. Maternal stress can also affect the development of the stress axis in offspring leading to alterations in their physiological stress response. However, the majority of evidence comes from studies utilising acute stressors or exogenous glucocorticoids, and little is known about the effect of chronic maternal stress, particularly in the context of stress lasting throughout entire reproductive lifespan. To bridge this knowledge gap, we exposed female sticklebacks to stressful and unpredictable environmental conditions throughout the breeding season. We quantified the activity, sheltering and anxiety-like behaviour of offspring from three successive clutches of these females, and calculated Intra-class Correlation Coefficients for these behaviours in siblings and half-siblings. We also exposed offspring to an acute stressor and measured their peak cortisol levels. An unpredictable maternal environment had no modifying effect on inter-clutch acute stress responsivity, but resulted in diversification of offspring behaviour, indicated by an increased between-individual variability within families. This may represent a bet-hedging strategy, whereby females produce offspring differing in behavioural phenotype, to increase the chance that some of these offspring will be better at coping with the anticipated conditions.

Implications of reducing antibiotic treatment duration for antimicrobial resistance in hospital settings: A modelling study and meta-analysis.

BACKGROUND: Reducing antibiotic treatment duration is a key component of hospital antibiotic stewardship interventions. However, its effectiveness in reducing antimicrobial resistance is uncertain and a clear theoretical rationale for the approach is lacking. In this study, we sought to gain a mechanistic understanding of the relation between antibiotic treatment duration and the prevalence of colonisation with antibiotic-resistant bacteria in hospitalised patients. METHODS AND FINDINGS: We constructed 3 stochastic mechanistic models that considered both between- and within-host dynamics of susceptible and resistant gram-negative bacteria, to identify circumstances under which shortening antibiotic duration would lead to reduced resistance carriage. In addition, we performed a meta-analysis of antibiotic treatment duration trials, which monitored resistant gram-negative bacteria carriage as an outcome. We searched MEDLINE and EMBASE for randomised controlled trials published from 1 January 2000 to 4 October 2022, which allocated participants to varying durations of systemic antibiotic treatments. Quality assessment was performed using the Cochrane risk-of-bias tool for randomised trials. The meta-analysis was performed using logistic regression. Duration of antibiotic treatment and time from administration of antibiotics to surveillance culture were included as independent variables. Both the mathematical modelling and meta-analysis suggested modest reductions in resistance carriage could be achieved by reducing antibiotic treatment duration. The models showed that shortening duration is most effective at reducing resistance carriage in high compared to low transmission settings. For treated individuals, shortening duration is most effective when resistant bacteria grow rapidly under antibiotic selection pressure and decline rapidly when stopping treatment. Importantly, under circumstances whereby administered antibiotics can suppress colonising bacteria, shortening antibiotic treatment may increase the carriage of a particular resistance phenotype. We identified 206 randomised trials, which investigated antibiotic duration. Of these, 5 reported resistant gram-negative bacteria carriage as an outcome and were included in the meta-analysis. The meta-analysis determined that a single additional antibiotic treatment day is associated with a 7% absolute increase in risk of resistance carriage (80% credible interval 3% to 11%). Interpretation of these estimates is limited by the low number of antibiotic duration trials that monitored carriage of resistant gram-negative bacteria, as an outcome, contributing to a large credible interval. CONCLUSIONS: In this study, we found both theoretical and empirical evidence that reducing antibiotic treatment duration can reduce resistance carriage, though the mechanistic models also highlighted circumstances under which reducing treatment duration can, perversely, increase resistance. Future antibiotic duration trials should monitor antibiotic-resistant bacteria colonisation as an outcome to better inform antibiotic stewardship policies.

Patient Tailored Surgery in Saethre-Chotzen Syndrome: Analysis of Reoperation for Intracranial Hypertension.

Saethre-Chotzen syndrome (SCS) is a syndromic craniosynostosis with pathogenic variants in the TWIST1 gene showing a broad phenotypic spectrum. Controversies exist in the literature regarding surgical management with single one-stage versus patient-tailored surgery and the related reoperation rate for intracranial hypertension of up to 42%. At our center, SCS patients are offered patient-tailored surgery with single-stage fronto-orbital advancement and remodeling or fronto-orbital advancement and remodeling and posterior distraction in an individually determined order. The authors' database identified 35 confirmed SCS patients between 1999 and 2022. Involved sutures in craniosynostosis were left unicoronal (22.9%), bicoronal (22.9%), sagittal (8.6%), bicoronal and sagittal (5.7%), right unicoronal (2.9%), bicoronal and metopic (2.9%), bicoronal, sagittal and metopic (2.9%), and bilateral lambdoid (2.9%). There was pansynostosis in 8.6% and no craniosynostosis in 14.3% of the patients. Twenty-six patients, 10 females, and 16 males were operated on. Mean age at the first surgery was 1.70 years, and 3.86 years at the second surgery. Eleven of 26 patients had invasive intracranial pressure monitoring. Three patients presented with papilledema before the first surgery and 4 afterward. Four of the 26 operated patients were operated initially elsewhere. The other 22 patients were initially referred to our unit and underwent patient-tailored surgery. Nine of these patients (41%) had a second surgery, and 3 (14%) of them were because of raised intracranial pressure. Seven (27%) of all operated patients had a complication. Median follow-up was 13.98 years (range, 1.85-18.08). Patient-tailored surgery in a specialized center and long-term follow-up allow for a low reoperation rate for intracranial hypertension.

National Dog Survey: Describing UK Dog and Ownership Demographics.

With dogs being the most commonly owned companion animal in the United Kingdom, knowledge about dog demographics is important in understanding the impact of dogs on society. Furthermore, understanding the demography of dog owners is also important to better target support to dogs and their owners to achieve optimal welfare in the canine population. Combining natural fluctuations in the population and unprecedented events such as the COVID-19 pandemic, the need for an up-to-date large-scale dataset is even more paramount. In order to address this, Dogs Trust launched the 'National Dog Survey' to provide a large population-level dataset that will help identify key areas of concern and needs of owners and their dogs. The online survey was completed by a total of 354,046 respondents owning dogs in the UK, providing data for 440,423 dogs. The results of this study highlight dog demographics, including acquisition and veterinary factors, as well as owner demographic and household information. Finally, general trends in ownership, and more specifically those following the COVID-19 pandemic, are described. This paper's findings provide valuable insight into the current population of dogs and their owners in the UK, allowing for the most appropriate products, services, interventions and regulations to be developed, reducing the likelihood of negative welfare outcomes such as health and behaviour issues, relinquishment or euthanasia. Furthermore, with significant changes to the dog population following the COVID-19 pandemic highlighted, this dataset serves as an up-to-date baseline for future study comparisons to continue to monitor trends and patterns of the dog population and dog owners going forwards.

Non-pharmacological treatment options of drug-resistant epilepsy in subcortical band heterotopia: systematic review and illustrative case.

OBJECTIVE: Subcortical band heterotopia is a rare X-linked neuronal migration disorder primarily in females often associated with drug-resistant epilepsy. The aim of this study is to review the literature for non-pharmacological treatment options of drug-resistant epilepsy in subcortical band heterotopia. MATERIAL AND METHODS: In accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we performed a systematic review. Entering the keywords "double cortex," "subcortical band heterotopia," and "subcortical laminar heterotopia," we searched Scopus and PubMed databases. We paid particular attention to type of invasive and non-invasive treatment, radiological presentation, and outcome. We also describe a related case report, managed at Alder Hey Children's Hospital, Liverpool. RESULTS: The systematic literature review yielded 25 patients with subcortical band heterotopia and drug-resistant epilepsy who underwent non-pharmacological treatment. Including our patient, 26 patients were reported. The patients' mean age at seizure onset was 6.5 years (range 0.2-23) with a female sex predilection (5.25:1). The patients' mean age at invasive or non-invasive treatment was 21.5 years (range 6.5-51). The 26 patients underwent 29 non-pharmacological treatments. Ten patients underwent corpus callosotomy; 8 patients had a formal temporal lobectomy. Three patients had focal cortical resection. Two patients respectively had multiple subpial transections, insertion of a vagal nerve stimulator, or deep brain stimulation of the bilateral anterior nuclei of the thalamus. One patient underwent responsive focal neurostimulation. Another patient had transcutaneous stimulation of the vagal nerve. Sixteen patients reported a reduction or the disappearance of the seizures; 1 patient had no improvement. The outcome of 2 patients was classified class I, of 1 patient class II, of 1 patient class III, and of 5 patients class IV according to the Engel Epilepsy Surgery Outcome Scale. CONCLUSION: Mainly corpus callosotomy and formal temporal lobectomy have been performed as non-pharmacological treatment with few cases published overall. Several other invasive procedures and one non-invasive technique are based on case reports. The small number of reported cases prevents drawing a firm conclusion as to which non-pharmacological treatment is the best treatment option for refractive epilepsy in patients with subcortical band heterotopia.

Estimation of the impact of hospital-onset SARS-CoV-2 infections on length of stay in English hospitals using causal inference.

BACKGROUND: From March 2020 through August 2021, 97,762 hospital-onset SARS-CoV-2 infections were detected in English hospitals. Resulting excess length of stay (LoS) created a potentially substantial health and economic burden for patients and the NHS, but we are currently unaware of any published studies estimating this excess. METHODS: We implemented appropriate causal inference methods to determine the extent to which observed additional hospital stay is attributable to the infection rather than the characteristics of the patients. Hospital admissions records were linked to SARS-CoV-2 test data to establish the study population (7.5 million) of all non-COVID-19 admissions to English hospitals from 1st March 2020 to 31st August 2021 with a stay of at least two days. The excess LoS due to hospital-onset SARS-CoV-2 infection was estimated as the difference between the mean LoS observed and in the counterfactual where infections do not occur. We used inverse probability weighted Kaplan-Meier curves to estimate the mean survival time if all hospital-onset SARS-CoV-2 infections were to be prevented, the weights being based on the daily probability of acquiring an infection. The analysis was carried out for four time periods, reflecting phases of the pandemic differing with respect to overall case numbers, testing policies, vaccine rollout and prevalence of variants. RESULTS: The observed mean LoS of hospital-onset cases was higher than for non-COVID-19 hospital patients by 16, 20, 13 and 19 days over the four phases, respectively. However, when the causal inference approach was used to appropriately adjust for time to infection and confounding, the estimated mean excess LoS caused by hospital-onset SARS-CoV-2 was: 2.0 [95% confidence interval 1.8-2.2] days (Mar-Jun 2020), 1.4 [1.2-1.6] days (Sep-Dec 2020); 0.9 [0.7-1.1] days (Jan-Apr 2021); 1.5 [1.1-1.9] days (May-Aug 2021). CONCLUSIONS: Hospital-onset SARS-CoV-2 is associated with a small but notable excess LoS, equivalent to 130,000 bed days. The comparatively high LoS observed for hospital-onset COVID-19 patients is mostly explained by the timing of their infections relative to admission. Failing to account for confounding and time to infection leads to overestimates of additional length of stay and therefore overestimates costs of infections, leading to inaccurate evaluations of control strategies.

A scoping review of antibiotic use practices and drivers of inappropriate antibiotic use in animal farms in WHO Southeast Asia region.

Antibiotic use (ABU) plays an important role in the proliferation of antimicrobial resistance (AMR). Global antimicrobial consumption in food production is projected to rise by 67% from 2010 to 2030, but available estimates are limited by the scarcity of ABU data and absence of global surveillance systems. The WHO South-East Asia (WHO SEA) region is at high risk of emergence of AMR, likely driven by intensifying farm operations and worsening ABU hotspots. However, little is known about farm-level ABU practices in the region. To summarize emerging evidence and research gaps, we conducted a scoping review of ABU practices following the Arksey and O'Malley methodological framework. We included studies published between 2010 and 2021 on farm-level ABU/AMR in the 11 WHO SEA member states, and databases were last searched on 31 October 2021. Our search strategy identified 184 unique articles, and 25 publications underwent full-text eligibility assessment. Seventeen studies, reported in 18 publications, were included in the scoping review. We found heterogeneity in the categorizations, definitions, and ABU characterization methods used across studies and farm types. Most studies involved poultry, pig, and cattle farms, and only one study examined aquaculture. Most studies evaluated ABU prevalence by asking respondents about the presence or absence of ABU in the farm. Only two studies quantified antibiotic consumption, and sampling bias and lack of standardized data collection methods were identified as key limitations. Emerging evidence that farm workers had difficulty differentiating antibiotics from other substances contributed to the uncertainty about the reliability of self-reported data without other validation techniques. ABU for growth promotion and treatment were prevalent. We found a large overlap in the critically important antibiotics used in farm animals and humans. The ease of access to antibiotics compounded by the difficulties in accessing quality veterinary care and preventive services likely drive inappropriate ABU in complex ways.

Excess Mortality Attributable to Hospital-Acquired Antimicrobial-Resistant Infections: A 2-Year Prospective Surveillance Study in Northeast Thailand.

Background: Quantifying the excess mortality attributable to antimicrobial-resistant (AMR) bacterial infections is important for assessing the potential benefit of preventive interventions and for prioritization of resources. However, there are few data from low- and middle-income countries. Methods: We conducted a 2-year prospective surveillance study to estimate the excess mortality attributable to AMR infections for all types of hospital-acquired infection (HAI), and included bacterial species that were both locally relevant and included in the World Health Organization priority list. Twenty-eight-day mortality was measured. Excess mortality and population attributable fraction (PAF) of mortality caused by AMR infections compared to antimicrobial-susceptible (AMS) infections, adjusted for predefined confounders, were calculated. Results: We enrolled 2043 patients with HAIs. The crude 28-day mortality of patients with AMR and AMS infections was 35.5% (491/1385) and 23.1% (152/658), respectively. After adjusting for prespecified confounders, the estimated excess mortality attributable to AMR infections was 7.7 (95% confidence interval [CI], 2.2-13.2) percentage points. This suggests that 106 (95% CI, 30-182) deaths among 1385 patients with AMR infections might have been prevented if all of the AMR infections in this study were AMS infections. The overall PAF was 16.3% (95% CI, 1.2%-29.1%). Among the bacteria under evaluation, carbapenem-resistant Acinetobacter baumannii was responsible for the largest number of excess deaths. Among all types of infection, urinary tract infections were associated with the highest number of excess deaths, followed by lower respiratory tract infections and bloodstream infections. Conclusions: Estimating and monitoring excess mortality attributable to AMR infections should be included in national action plans to prioritize targets of preventive interventions. Clinical Trials Registration: NCT03411538.

Screening Biophysical Sensors and Neurite Outgrowth Actuators in Human Induced-Pluripotent-Stem-Cell-Derived Neurons.

All living cells maintain a charge distribution across their cell membrane (membrane potential) by carefully controlled ion fluxes. These bioelectric signals regulate cell behavior (such as migration, proliferation, differentiation) as well as higher-level tissue and organ patterning. Thus, voltage gradients represent an important parameter for diagnostics as well as a promising target for therapeutic interventions in birth defects, injury, and cancer. However, despite much progress in cell and molecular biology, little is known about bioelectric states in human stem cells. Here, we present simple methods to simultaneously track ion dynamics, membrane voltage, cell morphology, and cell activity (pH and ROS), using fluorescent reporter dyes in living human neurons derived from induced neural stem cells (hiNSC). We developed and tested functional protocols for manipulating ion fluxes, membrane potential, and cell activity, and tracking neural responses to injury and reinnervation in vitro. Finally, using morphology sensor, we tested and quantified the ability of physiological actuators (neurotransmitters and pH) to manipulate nerve repair and reinnervation. These methods are not specific to a particular cell type and should be broadly applicable to the study of bioelectrical controls across a wide range of combinations of models and endpoints.

Attributable mortality and excess length of stay associated with third-generation cephalosporin-resistant Enterobacterales bloodstream infections: a prospective cohort study in Suva, Fiji.

OBJECTIVES: There are scant primary clinical data on antimicrobial resistance (AMR) burden from low- and middle-income countries (LMICs). We adapted recent World Health Organization methodology to measure the effect of third-generation cephalosporin resistance (3GC-R) on mortality and excess length of hospital stay in Fiji. METHODS: We conducted a prospective cohort study of inpatients with Enterobacterales bloodstream infections (BSIs) at Colonial War Memorial Hospital, Suva. We used cause-specific Cox proportional hazards models to estimate the effect of 3GC-R on the daily risk (hazard) of in-hospital mortality and being discharged alive (competing risks), and we used multistate modelling to estimate the excess length of hospital stay. RESULTS: From July 2020 to February 2021 we identified 162 consecutive Enterobacterales BSIs; 3GC-R was present in 66 (40.7%). Crude mortality for patients with 3GC-susceptible and 3GC-R BSIs was 16.7% (16/96) and 30.3% (20/66), respectively. 3GC-R was not associated with the in-hospital mortality hazard rate (adjusted hazard ratio [aHR] 1.13, 95% confidence interval [CI] 0.51-2.53) or being discharged alive (aHR 0.99, 95% CI 0.65-1.50), whereas Charlson comorbidity index score (aHR 1.62, 95% CI 1.36-1.93) and Pitt bacteraemia score (aHR 3.57, 95% CI 1.31-9.71) were both associated with an increased hazard rate of in-hospital mortality. 3GC-R was associated with an increased length of stay of 2.6 days (95% CI 2.5-2.8). 3GC-R was more common among hospital-associated infections, but genomics did not identify clonal transmission. CONCLUSION: Patients with Enterobacterales BSIs in Fiji had high mortality. There were high rates of 3GC-R, which was associated with increased hospital length of stay but not with in-hospital mortality.

The contribution of hospital-acquired infections to the COVID-19 epidemic in England in the first half of 2020.

BACKGROUND: SARS-CoV-2 is known to transmit in hospital settings, but the contribution of infections acquired in hospitals to the epidemic at a national scale is unknown. METHODS: We used comprehensive national English datasets to determine the number of COVID-19 patients with identified hospital-acquired infections (with symptom onset > 7 days after admission and before discharge) in acute English hospitals up to August 2020. As patients may leave the hospital prior to detection of infection or have rapid symptom onset, we combined measures of the length of stay and the incubation period distribution to estimate how many hospital-acquired infections may have been missed. We used simulations to estimate the total number (identified and unidentified) of symptomatic hospital-acquired infections, as well as infections due to onward community transmission from missed hospital-acquired infections, to 31st July 2020. RESULTS: In our dataset of hospitalised COVID-19 patients in acute English hospitals with a recorded symptom onset date (n = 65,028), 7% were classified as hospital-acquired. We estimated that only 30% (range across weeks and 200 simulations: 20-41%) of symptomatic hospital-acquired infections would be identified, with up to 15% (mean, 95% range over 200 simulations: 14.1-15.8%) of cases currently classified as community-acquired COVID-19 potentially linked to hospital transmission. We estimated that 26,600 (25,900 to 27,700) individuals acquired a symptomatic SARS-CoV-2 infection in an acute Trust in England before 31st July 2020, resulting in 15,900 (15,200-16,400) or 20.1% (19.2-20.7%) of all identified hospitalised COVID-19 cases. CONCLUSIONS: Transmission of SARS-CoV-2 to hospitalised patients likely caused approximately a fifth of identified cases of hospitalised COVID-19 in the "first wave" in England, but less than 1% of all infections in England. Using time to symptom onset from admission for inpatients as a detection method likely misses a substantial proportion (> 60%) of hospital-acquired infections.