Inline dynamometry provides reliable measurements of quadriceps strength in healthy and ACL-reconstructed individuals and is a valid substitute for isometric electromechanical dynamometry following ACL reconstruction.

BACKGROUND: Quadriceps strength testing is recommended to guide rehabilitation and mitigate the risk of second injury following anterior cruciate ligament (ACL) reconstruction. Hand-held dynamometry is a practical alternative to electromechanical dynamometry but demonstrates insufficient reliability and criterion validity in healthy and ACL-reconstructed participants respectively. The purpose of this study is to investigate the reliability and concurrent validity of inline dynamometry for measuring quadriceps strength. The hypotheses are that intra-class correlation coefficient (ICC) values will be >0.90 for reliability and concurrent validity. METHODS: This was a cross sectional study using a within-participant, repeated measures design. Isometric quadriceps testing was performed at 60° knee flexion in 50 healthy and 52 ACL-reconstructed participants. Interrater reliability, intrarater reliability, and concurrent validity of inline dynamometry was investigated through calculation of ICCs, Bland-Altman analysis, linear regression, standard error of measurement (SEM) and minimal detectable change (MDC). RESULTS: The lower bounds of the 95% confidence intervals were >0.90 for all reliability and validity ICCs in healthy and ACL-reconstructed participants, except for intrarater reliability in healthy participants using absolute scores (ICC = 0.936 [95% CI 0.890-0.963]). In ACL-reconstructed participants, Bland-Altman bias was 0.01 Nm/kg for absolute and average scores, limits of agreement were -11.74% to 12.59% for absolute scores, the SEM was 0.13Nm/kg (95% CI 0.10-0.17) and the MDC was 0.36Nm/kg (95% CI 0.28 - 0.47). CONCLUSION: Inline dynamometry is a reliable and economical alternative to electromechanical dynamometry for the assessment of quadriceps strength following ACL-reconstruction. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT05109871).

Persistent Firing in Hippocampal CA1 Pyramidal Cells in Young and Aged Rats.

Persistent neuronal firing is often observed in working memory and temporal association tasks both in humans and animals, and is believed to retain necessary information in these tasks. We have reported that hippocampal CA1 pyramidal cells are able to support persistent firing through intrinsic mechanisms in the presence of cholinergic agonists. However, it still remains largely unknown how persistent firing is affected by the development of animals and aging. Using in vitro patch-clamp recordings from CA1 pyramidal cells in rat brain slices, we first show that the cellular excitability of these aged rats was significantly lower than that of the young rats, responding with fewer spikes to current injection. In addition, we found age-dependent modulations of input resistance, membrane capacitance, and spike width. However, persistent firing in aged (approximately two-year-old) rats was as strong as that in young animals, and the properties of persistent firing were very similar among different age groups. In addition, medium spike afterhyperpolarization potential (mAHP), was not increased by aging and did not correlate with the strength of persistent firing. Lastly, we estimated the depolarization current induced by the cholinergic activation. This current was proportional to the increased membrane capacitance of the aged group and was inversely correlated with their intrinsic excitability. These observations indicate that robust persistent firing can be maintained in aged rats despite reduced excitability, because of the increased amount of cholinergically induced positive current.

First Responder Virtual Reality Simulator to train and assess emergency personnel for mass casualty response.

As mass casualty incidents continue to escalate in the United States, we must improve frontline responder performance to increase the odds of victim survival. In this article, we describe the First Responder Virtual Reality Simulator, a high-fidelity, fully immersive, automated, programmable virtual reality (VR) simulation designed to train frontline responders to treat and triage victims of mass casualty incidents. First responder trainees don a wireless VR head-mounted display linked to a compatible desktop computer. Trainees see and hear autonomous, interactive victims who are programmed to simulate individuals with injuries consistent with an explosion in an underground space. Armed with a virtual medical kit, responders are tasked with triaging and treating the victims on the scene. The VR environment can be made more challenging by increasing the environmental chaos, adding patients, or increasing the acuity of patient injuries. The VR platform tracks and records their performance as they navigate the disaster scene. Output from the system provides feedback to participants on their performance. Eventually, we hope that the First Responder system will serve both as an effective replacement for expensive conventional training methods as well as a safe and efficient platform for research on current triage protocols.

Evaluation of a pharmacy supported e-cigarette smoking cessation intervention in Northwest England.

BACKGROUND: Cigarette smoking cessation has been described as the world's most important public health intervention. Electronic cigarettes are a relatively new tool for assisting smoking cessation but there is a lack of data on their efficacy. This article reports on a pharmacy supported e-cigarette smoking cessation intervention undertaken in a metropolitan area in the north of England. METHODS: Longitudinal mixed-methods evaluation incorporating analysis of secondary data, interviews with service users, and interviews with service providers at 3-month and 12-month follow-up, with an additional text message survey of service users at 12-month follow-up. RESULTS: The four-week follow-up data suggest that for every twenty people given an e-cigarette, six quit smoking tobacco and three people cut their cigarette intake by more than five cigarettes per day. Long-term follow-up results were positive but only a small number of participants were still engaged with the study at 12 months. Service users and providers spoke positively about the combination of e-cigarettes and pharmacy support. CONCLUSIONS: E-cigarette distribution combined with pharmacy support appears to be an agreeable and effective intervention for smoking cessation, but further data are needed on long-term quit rates and health effects.

The repurposing of Tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively drug-resistant Shigella spp.

Background: Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified Shigella spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for Shigella infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. Methods: Aiming to identify alternative antimicrobial chemicals with activity against antimicrobial resistant Shigella, we initiated a collaborative academia-industry drug discovery project, applying high-throughput phenotypic screening across broad chemical diversity and followed a lead compound through in vitro and in vivo characterisation. Results: We identified several known antimicrobial compound classes with antibacterial activity against Shigella. These compounds included the oral carbapenem Tebipenem, which was found to be highly potent against broadly susceptible Shigella and contemporary MDR variants for which we perform detailed pre-clinical testing. Additional in vitro screening demonstrated that Tebipenem had activity against a wide range of other non-Shigella enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating Tebipenem. We found the orally bioavailable prodrug (Tebipenem pivoxil) had ideal pharmacokinetic properties for treating enteric pathogens and was effective in clearing the gut of infecting organisms when administered to Shigella-infected mice and gnotobiotic piglets. Conclusions: Our data highlight the emerging antimicrobial resistance crisis and shows that Tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) should be accelerated into human trials and could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs. Funding: Tres Cantos Open Lab Foundation (projects TC239 and TC246), the Bill and Melinda Gates Foundation (grant OPP1172483) and Wellcome (215515/Z/19/Z).

Prevalence of fetal alcohol spectrum disorder in Greater Manchester, UK: An active case ascertainment study.

BACKGROUND: Despite high levels of prenatal alcohol exposure in the UK, evidence on the prevalence of fetal alcohol spectrum disorders (FASD) is lacking. This paper reports on FASD prevalence in a small sample of children in primary school. METHODS: A 2-phase active case ascertainment study was conducted in 3 mainstream primary schools in Greater Manchester, UK. Schools were located in areas that ranged from relatively deprived to relatively affluent. Initial screening of children aged 8-9 years used prespecified criteria for elevated FASD risk (small for age; special educational needs; currently/previously in care; significant social/emotional/mental health symptoms). Screen-positive children were invited for detailed ascertainment of FASD using gold standard measures that included medical history, facial dysmorphology, neurological impairment, executive function, and behavioral difficulties. RESULTS: Of 220 eligible children, 50 (23%) screened positive and 12% (26/220) proceeded to Phase 2 assessment. Twenty had a developmental disorder, of whom 4 had FASD and 4 were assessed as possible FASD. The crude prevalence rate of FASD in these schools was 1.8% (95% CI: 1.0%, 3.4%) and when including possible cases was 3.6% (2.1%, 6.3%). None of these children had previously been identified with a developmental diagnosis. CONCLUSIONS: FASD was found to be common in these schools and most of these children's needs had not previously been identified. A larger, more definitive study that uses a random sampling technique stratified by deprivation level to select schools is needed to make inferences regarding the population prevalence of FASD.

Enhanced modulation of cell-type specific neuronal responses in mouse dorsal auditory field during locomotion.

As we move through the environment we experience constantly changing sensory input that must be merged with our ongoing motor behaviors - creating dynamic interactions between our sensory and motor systems. Active behaviors such as locomotion generally increase the sensory-evoked neuronal activity in visual and somatosensory cortices, but evidence suggests that locomotion largely suppresses neuronal responses in the auditory cortex. However, whether this effect is ubiquitous across different anatomical regions of the auditory cortex is largely unknown. In mice, auditory association fields such as the dorsal auditory cortex (AuD), have been shown to have different physiological response properties, protein expression patterns, and cortical as well as subcortical connections, in comparison to primary auditory regions (A1) - suggesting there may be important functional differences. Here we examined locomotion-related modulation of neuronal activity in cortical layers ⅔ of AuD and A1 using two-photon Ca2+ imaging in head-fixed behaving mice that are able to freely run on a spherical treadmill. We determined the proportion of neurons in these two auditory regions that show enhanced and suppressed sensory-evoked responses during locomotion and quantified the depth of modulation. We found that A1 shows more suppression and AuD more enhanced responses during locomotion periods. We further revealed differences in the circuitry between these auditory regions and motor cortex, and found that AuD is more highly connected to motor cortical regions. Finally, we compared the cell-type specific locomotion-evoked modulation of responses in AuD and found that, while subpopulations of PV-expressing interneurons showed heterogeneous responses, the population in general was largely suppressed during locomotion, while excitatory population responses were generally enhanced in AuD. Therefore, neurons in primary and dorsal auditory fields have distinct response properties, with dorsal regions exhibiting enhanced activity in response to movement. This functional distinction may be important for auditory processing during navigation and acoustically guided behavior.

Fetal alcohol spectrum disorders: an overview of current evidence and activities in the UK.

Estimates for the UK suggest that alcohol consumption during pregnancy and prevalence of fetal alcohol spectrum disorder (FASD)-the most common neurodevelopmental condition-are high. Considering the significant health and social impacts of FASD, there is a public health imperative to prioritise prevention, interventions and support. In this article, we outline the current state of play regarding FASD knowledge and research in the UK, which is characterised by a lack of evidence, a lack of dedicated funding and services, and consequently little policy formulation and strategic direction. We highlight progress made to date, as well as current knowledge and service gaps to propose a way forward for UK research.

The BaSICS (Baby Skin Integrity Comparison Survey) study: A prospective experimental study using maternal observations to report the effect of baby wipes on the incidence of irritant diaper dermatitis in infants, from birth to eight weeks of age.

BACKGROUND: Baby wipes have been shown to be safe and effective in maintaining skin integrity when compared to the use of water alone. However, no previous study has compared different formulations of wipe. The aim of the BaSICS study was to identify any differences in incidence of irritant diaper dermatitis (IDD) in infants assigned to three different brands of wipe, all marketed as suitable for neonates, but which contained varying numbers of ingredients. METHODS: Women were recruited during the prenatal period. Participants were randomly assigned to receive one of three brands of wipe for use during the first eight weeks following childbirth. All participants received the same nappies. Participants reported their infant's skin integrity on a scale of 1-5 daily using a bespoke smartphone application. Analysis of effect of brand on clinically significant IDD (score 3 or more) incidence was conducted using a negative binomial generalised linear model, controlling for possible confounders at baseline. Analysts were blind to brand of wipe. RESULTS: Of 737 women enrolled, 15 were excluded (admitted to neonatal intensive care, premature or other infant health issues). Of the 722 eligible babies, 698 (97%) remained in the study for the full 8-week duration, 24.6% of whom had IDD at some point during the study. Mothers using the brand with the fewest ingredients reported fewer days of clinically significant nappy rash (score≥3) than participants using the two other brands (p = 0.002 and p < 0.001). Severe IDD (grades 4 and 5) was rare (2.4%). CONCLUSIONS: Rarity of severe IDD suggested that sensitive formula baby wipes are safe when used in cleansing babies from birth to eight weeks during nappy changes. The brand with fewest ingredients had significantly fewer days of clinically significant IDD. Daily observations recorded on a smartphone application proved to be a highly acceptable method of obtaining real-time data on IDD. CLINICAL TRIAL REGISTRATION: This study was not designed or registered as a clinical trial as no intervention in normal patterns of infant care took place. Mothers who had already decided to use disposable nappies and a baby wipe product agreed to observe and report on their infants' skin condition; in return they received a 9-week supply of free nappies and wipes.

Social prescribing for people with mental health needs living in disadvantaged communities: the Life Rooms model.

BACKGROUND: People live socially complex lives and have different health care needs influenced by socio-economic factors such as deprivation, unemployment, and poor housing. Lack of access to community based social care results in people seeking social support from health care services. This study explores the Life Rooms as a social prescribing model addressing the social determinants of mental health by providing support and access to resources in a local community setting. With an aim to identify key elements that contribute toward enhancing the effectiveness of the Life Rooms social prescribing approach. METHODS: Data were obtained through six semi-structured focus groups with mental health service users from two locations in the North West of the UK. Postcode data was collected to generate an Index for Multiple Deprivation (IMD) score, to understand their socio-economic background. Data were analysed using thematic analysis. RESULTS: A total of 18 participants took part in the study. The majority of participants came from disadvantaged backgrounds; 14 participants measuring 3 and below in terms of overall IMD scores and 9 participants belonged to the poorest decile (IMD score = 1). Participants reported on different elements of the Life Rooms which they found as an effective approach to care. Four main themes emerged from the data: 1) social belonging: being able to just 'be' 2) resourceful and accessible; 3) social inclusion and connectedness; and 4) moving forward: self-development and independence. CONCLUSION: Findings support the need and benefit social prescribing to improve mental health wellbeing and reduce the burden of mental illness.

Neurodevelopmental outcomes in individuals with fetal alcohol spectrum disorder (FASD) with and without exposure to neglect: Clinical cohort data from a national FASD diagnostic clinic.

Disentangling the relative developmental impact of prenatal alcohol exposure from postnatal neglect is clinically valuable for informing future service provision. In this study, developmental outcomes across groups are compared in a 'natural experiment'. METHODS: Clinical data from 99 persons with fetal alcohol spectrum disorder (FASD) diagnoses were audited. Developmental outcomes (diagnosis of attention deficit hyperactivity disorder, ADHD; social and communication disorder, SCD; or Autistic Spectrum Disorder, ASD; Short Sensory Profile, SSP; Vineland II Adaptive Behaviour Scales) were compared across two exposure groups: prenatal alcohol only; and mixed prenatal alcohol and neglect. RESULTS: ADHD (74%) and ASD/SCD (68%) were common, with no significant difference between groups (ADHD, p = 0.924; ASD, p = 0.742). Vineland age equivalence scores were lower than chronological age (11.1 years - prenatal alcohol only, and 12.7 years - neglect) across all domains, especially receptive language (3.7 years for both groups). Age equivalence did not differ between groups, with the exception of domestic daily living (neglect: 7.7 years vs. prenatal alcohol only: 5.8 years, p = 0.027). A probable/definite difference on SSP was more common in the prenatal alcohol only (96% vs. 67%, p = 0.006). For the individual subscales of SSP, there were no significant differences by neglect category. DISCUSSION: Postnatal neglect in this group did not make the developmental outcome any worse, suggesting that prenatal alcohol influences these outcomes independently. Professionals who support families looking after a child with both FASD and a history of neglect should be aware that the behavioral difficulties are likely to be related to prenatal alcohol exposure and not necessarily reflective of parenting quality.

Developing a Conversational Virtual Standardized Patient to Enable Students to Practice History-Taking Skills.

INTRODUCTION: Although traditional virtual patient simulations are designed to teach and assess clinical reasoning skills, few employ conversational dialogue with the patients. The virtual standardized patients (VSPs) described herein represent standardized patients that students interview using natural language. Students take histories and develop differential diagnoses of the VSPs as much as they would with standardized or actual patients. The student-VSP interactions are recorded, creating a comprehensive record of questions and the order in which they were asked, which can be analyzed to assess information-gathering skills. Students document the encounter in an electronic medical record created for the VSPs. METHODS: The VSP was developed by integrating a dialogue management system (ChatScript) with emotionally responsive 3D characters created in a high-fidelity game engine (Unity). The system was tested with medical students at the Ohio State University College of Medicine. Students are able to take a history of a VSP, develop a differential diagnosis, and document the encounter in the electronic medical record. RESULTS: Accuracy of the VSP responses ranged from 79% to 86%, depending on the complexity of the case, type of history obtained, and skill of the student. Students were able to accurately develop an appropriate differential diagnosis on the basis of the information provided by the patient during the encounter. CONCLUSIONS: The VSP enables students to practice their history-taking skills before encounters with standardized or actual patients. Future developments will focus on creating an assessment module that will automatically analyze VSP sessions and provide immediate student feedback.

Prenatal alcohol exposure and traumatic childhood experiences: A systematic review.

Prenatal alcohol exposure (PAE) and traumatic childhood experiences (trauma) such as abuse or neglect can each cause central nervous system neurobiological changes or structural damage which can manifest as cognitive and behavioural dysfunction. In cases where both exposures have occurred, the risk of neurodevelopmental impairment may be greater, but this interaction has not been well studied. Here we present a systematic review that identified five primary research studies which investigated either the impact of trauma in children with PAE, or of PAE in children with trauma. Due to the heterogeneity of studies, narrative analysis was applied. Children in these cohorts with both exposures were more likely to show deficits in language, attention, memory and intelligence, and exhibit more severe behavioural problems than children with one exposure in absence of the other. However, the current literature is scarce and methodologically flawed. Further studies are required that: assess dual exposure in other neurodevelopmental domains; feature developmentally impaired yet non-exposed controls; and account for the wide spectrum of effects and different diagnostic criteria associated with PAE.

Implicit Alcohol-Related Expectancies and the Effect of Context.

OBJECTIVE: The current study examined the impact of varying pictorial cues and testing contexts on implicit alcohol-related expectancies. METHOD: Seventy-six participants were assigned randomly to complete an Implicit Relational Assessment Procedure (IRAP) in either a pub or lecture context. The IRAP exposed participants to pictorial cues that depicted an alcoholic beverage in the foreground of a pub (alcohol-congruent stimuli) or university lecture theater (alcohol-incongruent stimuli), and participants were required to match both positive and negative alcohol-related outcome expectancies to these stimuli. Corresponding to a 4 × 2 design, IRAP trial types were included in the analysis as repeated-measure variables, whereas testing environment was input as a between-participants variable. RESULTS: Participants more readily endorsed that drinking alcohol was related to positive expectancies when responding to alcohol-congruent stimuli, and this was strengthened when participants completed the task in a pub. Moreover, they more readily confirmed that alcohol was related to negative expectancies when responding to alcohol-incongruent stimuli. CONCLUSIONS: These findings suggest that alcohol-related cues and environmental contexts may be a significant driver of positive alcohol-related cognitions, which may have implications for the design of interventions. They emphasize further the importance of examining implicit cognitions in ecologically valid testing contexts.

"I have no clue what I drunk last night" using Smartphone technology to compare in-vivo and retrospective self-reports of alcohol consumption.

AIM: This research compared real-time measurements of alcohol consumption with retrospective accounts of alcohol consumption to examine possible discrepancies between, and contextual influences on, the different accounts. METHOD: Building on previous investigations, a specifically designed Smartphone technology was utilized to measure alcohol consumption and contextual influences in de facto real-time. Real-time data (a total of 10,560 data points relating to type and number of drinks and current social / environmental context) were compared with daily and weekly retrospective accounts of alcohol consumption. RESULTS: Participants reported consuming more alcoholic drinks during real-time assessment than retrospectively. For daily accounts a higher number of drinks consumed in real-time was related to a higher discrepancy between real-time and retrospective accounts. This effect was found across all drink types but was not shaped by social and environmental contexts. Higher in-vivo alcohol consumption appeared to be related to a higher discrepancy in retrospectively reported weekly consumption for alcohol beverage types other than wine. When including contextual factors into the statistical models, being with two or more friends (as opposed to being alone) decreased the discrepancy between real-time and retrospective reports, whilst being in the pub (relative to being at home) was associated with greater discrepancies. CONCLUSIONS: Overall, retrospective accounts may underestimate the amount of actual, real-time alcohol consumed. Increased consumption may also exacerbate differences between real-time and retrospective accounts. Nonetheless, this is not a global effect as environmental and social contexts interact with the type of alcohol consumed and the time frame given for reporting (weekly vs. daily retrospective). A degree of caution therefore appears warranted with regards to the use of retrospective self-report methods of recording alcohol consumption. Whilst real-time sampling is unlikely to be completely error free, it may be better able to account for social and environmental influences on self-reported consumption.

Is Radiotherapy Useful for Treating Pain in Mesothelioma?: A Phase II Trial.

INTRODUCTION: Radiotherapy is often used to treat pain in malignant pleural mesothelioma (MPM), although there is limited evidence to support this. The aim of this trial was to assess the role of radiotherapy for the treatment of pain in MPM. METHODS: A multicentre, single arm phase II trial was conducted. Eligible patients fulfilled the following criteria: pathological or radiological diagnosis of MPM; pain secondary to MPM; radiotherapy indicated for pain control; and more than 18 years of age. Patients had assessments of pain and other symptoms at baseline and then received 20 Gy in five daily fractions. Key follow-up points were 5 and 12 weeks posttreatment. The primary end point measure was assessment of pain at the site of radiotherapy at 5 weeks. Secondary end points included effects on quality of life, breathlessness, fatigue, mood, toxicity, and the radiological response. RESULTS: Forty patients were recruited from three UK oncology centers. Fourteen patients had a clinically meaningful improvement in their pain 5 weeks post radiotherapy (intention to treat), with five patients having a complete improvement. On the basis of a complete case analysis of the 30 patients assessable at week 5, 47% (confidence intervals, 28.3-65.7) of patients alive at week 5 had an improvement in their pain. There was no improvement in other key symptoms or quality of life. CONCLUSIONS: Radiotherapy for pain control in MPM is an effective treatment in a proportion of patients. Future studies examining differing radiotherapy regimens with a view to improving response rates are warranted.

Historical model for editor and Office of Research Integrity cooperation in handling allegations, investigation, and retraction in a contentious (Abbs) case of research misconduct.

Cooperation between a journal editor and the federal Office of Research Integrity (ORI) in addressing investigations of research misconduct, each performing their own responsibilities while keeping each other informed of events and evidence, can be critical to the professional and regulatory resolution of a case. This paper describes the history of one of ORI's most contentious investigations that involved falsification of research on Parkinson's disease patients by James Abbs, Professor of Neurology, University of Wisconsin, published in the journal Neurology, which was handled cooperatively by the authors, who were the chief ORI investigator and the Editor-in-Chief of Neurology, respectively.