Amyand's hernia with concurrent appendicitis: A case of interval laparoscopic herniorrhaphy and literature review.

INTRODUCTION AND IMPORTANCE: Amyand's hernia with concurrent appendicitis is rare, with a reported incidence of 0.13 % of all inguinal hernias. This condition is challenging to diagnose and manage and no optimal treatment has been established. CASE PRESENTATION: A 71-year-old man presented with an acutely painful, tender, and irreducible right inguinal hernia. He had a history of a right inguinal hernia for several months and had undergone open left inguinal hernia repair. The patient had no other medical comorbidities. Blood test results were nonspecific, with a C-reactive protein of 90 mg/L. Ultrasound scan suggested a strangulated right inguinal hernia. Laparoscopy revealed an Amyand's hernia with concurrent appendicitis and a pus-filled right inguinal hernia sac. The patient underwent laparoscopic appendicectomy, followed by staged laparoscopic transabdominal preperitoneal right inguinal hernia repair with mesh after eight weeks to reduce mesh infection. Histopathological examination confirmed acute uncomplicated appendicitis without perforation or malignancy. The patient had an unremarkable post-operative recovery. DISCUSSION: This case highlights the diagnostic challenges associated with Amyand's hernia and concurrent appendicitis. Laparoscopy provides both diagnostic and therapeutic opportunities. In this case, laparoscopic mesh herniorrhaphy was delayed and staged until local hernia sac inflammation resolved following appendicectomy. CONCLUSION: Surgeons should have an index of suspicion for Amyand's hernia given the heterogeneity of presentations. A case-by-case approach is required to prevent post-operative complications and determine the safe timing of definitive hernia repair when the inguinal hernial sac is inflamed. Further research is required to provide surgeons with evidence-based approaches for this unique condition.

Electrophysiological Phenotypes of Hippocampal Synaptic and Network Functions in Cannabinoid Receptor 2 Knockout Mice.

Background: The cannabinoid receptor 2 (CB2R), a cannabinoid receptor primarily expressed in immune cells, has been found in the brain, particularly in the hippocampus, where it plays crucial roles in modulating various neural functions, including synaptic plasticity, neuroprotection, neurogenesis, anxiety and stress responses, and neuroinflammation. Despite this growing understanding, the intricate electrophysiological characteristics of hippocampal neurons in CB2R knockout (CB2R KO) mice remain elusive. Aim and Methods: This study aimed to comprehensively assess the electrophysiological traits of hippocampal synaptic and network functions in CB2R KO mice. The focus was on aspects such as synaptic transmission, short- and long-term synaptic plasticity, and neural network synchrony (theta oscillations). Results: Our findings unveiled multiple functional traits in these CB2R KO mice, notably elevated synaptic transmission in hippocampal CA1 neurons, decreased both synaptic short-term plasticity (paired-pulse facilitation) and long-term potentiation (LTP), and impaired neural network synchronization. Conclusion: In essence, this study yields insightful revelations about the influence of CB2Rs on hippocampal neural functions. By illuminating the electrophysiological modifications in CB2R KO mice, our research enriches the comprehension of CB2R involvement in hippocampal function. Such insights could hold implications for advancing our understanding of the neural mechanisms under the influence of CB2Rs within the brain.

IMPAACT: IMproving the PArticipAtion of older people in policy decision-making on common health CondiTions - a study protocol.

INTRODUCTION: Rapid population ageing is a demographic trend being experienced and documented worldwide. While increased health screening and assessment may help mitigate the burden of illness in older people, issues such as misdiagnosis may affect access to interventions. This study aims to elicit the values and preferences of evidence-informed older people living in the community on early screening for common health conditions (cardiovascular disease, diabetes, dementia and frailty). The study will proceed in three Phases: (1) generating recommendations of older people through a series of Citizens' Juries; (2) obtaining feedback from a diverse range of stakeholder groups on the jury findings; and (3) co-designing a set of Knowledge Translation resources to facilitate implementation into research, policy and practice. Conditions were chosen to reflect common health conditions characterised by increasing prevalence with age, but which have been underexamined through a Citizens' Jury methodology. METHODS AND ANALYSIS: This study will be conducted in three Phases-(1) Citizens' Juries, (2) Policy Roundtables and (3) Production of Knowledge Translation resources. First, older people aged 50+ (n=80), including those from traditionally hard-to-reach and diverse groups, will be purposively recruited to four Citizen Juries. Second, representatives from a range of key stakeholder groups, including consumers and carers, health and aged care policymakers, general practitioners, practice nurses, geriatricians, allied health practitioners, pharmaceutical companies, private health insurers and community and aged care providers (n=40) will be purposively recruited for two Policy Roundtables. Finally, two researchers and six purposively recruited consumers will co-design Knowledge Translation resources. Thematic analysis will be performed on documentation and transcripts. ETHICS AND DISSEMINATION: Ethical approval has been obtained through the Torrens University Human Research Ethics Committee. Participants will give written informed consent. Findings will be disseminated through development of a policy brief and lay summary, peer-reviewed publications, conference presentations and seminars.

Effects of valproate on seizure-like activity in Drosophila melanogaster with a knockdown of Ube3a in different neuronal populations as a model of Angelman Syndrome.

Angelman Syndrome is a rare, genetically induced neurodevelopmental disorder. This disorder stems from a mutation or deletion of the maternal UBE3A gene. Characteristics of this disease include developmental delay, recurring seizures, and severe intellectual disabilities. We studied seizure activity in male Drosophila melanogaster with a knockdown of Ube3a in different neuronal populations (GABAergic, glutamatergic, mushroom body, and all neurons) and investigated the effects of the antiseizure medication (ASM) on seizure-like activity. Epileptiform activity was monitored in individual fruit flies using imaging chambers and mechanically induced seizures using a vortex assay. A positive control was also used: eas (easily shocked seizure phenotype). Seizure activity was analyzed for sums of seizure durations, number of seizures, and total time to return to normal activity. Ube3a knockdowns in GABAergic neurons elicited more seizure-like episodes than knockdowns in glutamatergic neurons and were on par with the positive control group and those with knockdowns in the mushroom bodies. We have established a method whereby valproate could be administered through food rather than through injections to effectively treat epileptiform activity. We demonstrated that if Ube3a is not knocked down pan-neuronally, Angelman Syndrome seizure-like activity can be studied using Drosophila melanogaster and therefore allows for high-throughput drug discovery.

Transcutaneous Auricular Vagus Nerve Stimulation Attenuates Early Increases in Heart Rate Associated With the Cold Pressor Test.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain. MATERIALS AND METHODS: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT. RESULTS: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS. CONCLUSIONS: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00113453.

Vacuum assisted closure with mesh mediated fascial traction of open abdominal wounds and acute fascial dehiscence, a single institution experience.

BACKGROUNDS: Laparostomy is a common means of managing surgical catastrophes, but often results in large ventral hernias which prove difficult to repair. It is also associated with high rates of enteric fistula formation. Dynamic methods of managing the open abdomen have been shown to result in higher rates of fascial closure and fewer complications. Recent publications have suggested the addition of chemical components relaxation with botulinum toxin has an added advantage over prior methods. METHODS: We report on a series of emergent cases managed by the combination of Botulinum toxin A (BTA) mediated chemical relaxation with a modified method of mesh-mediated fascial traction (MMFT) and negative pressure wound therapy (NPWT). RESULTS: Thirteen cases (nine laparostomies and four fascial dehiscence) were successfully closed in a median of 12 days, using a median of 4 'tightenings', with no clinical herniation detected at follow up so far (median 183 days, IQR 123-292). There were no procedure-related complications, but one death from the underling pathology. CONCLUSIONS: We report further cases of vacuum assisted mesh-mediated fascial traction (VA-MMFT) utilizing BTA in successfully managing laparostomy and abdominal wound dehiscence and continues the known high rate of successful fascial closure seen when applied in treating the open abdomen.

Providing multimedia information to children and young people increases recruitment to trials: pre-planned meta-analysis of SWATs.

BACKGROUND: Randomised controlled trials are often beset by problems with poor recruitment and retention. Information to support decisions on trial participation is usually provided as printed participant information sheets (PIS), which are often long, technical, and unappealing. Multimedia information (MMI), including animations and videos, may be a valuable alternative or complement to a PIS. The Trials Engagement in Children and Adolescents (TRECA) study compared MMI to PIS to investigate the effects on participant recruitment, retention, and quality of decision-making. METHODS: We undertook six SWATs (Study Within A Trial) within a series of host trials recruiting children and young people. Potential participants in the host trials were randomly allocated to receive MMI-only, PIS-only, or combined MMI + PIS. We recorded the rates of recruitment and retention (varying between 6 and 26 weeks post-randomisation) in each host trial. Potential participants approached about each host trial were asked to complete a nine-item Decision-Making Questionnaire (DMQ) to indicate their evaluation of the information and their reasons for participation/non-participation. Odds ratios were calculated and combined in a meta-analysis. RESULTS: Data from 3/6 SWATs for which it was possible were combined in a meta-analysis (n = 1758). Potential participants allocated to MMI-only were more likely to be recruited to the host trial than those allocated to PIS-only (OR 1.54; 95% CI 1.05, 2.28; p = 0.03). Those allocated to combined MMI + PIS compared to PIS-only were no more likely to be recruited to the host trial (OR = 0.89; 95% CI 0.53, 1.50; p = 0.67). Providing MMI rather than PIS did not impact on DMQ scores. Once children and young people had been recruited to host trials, their trial retention rates did not differ according to intervention allocation. CONCLUSIONS: Providing MMI-only increased the trial recruitment rate compared to PIS-only but did not affect DMQ scores. Combined MMI + PIS instead of PIS had no effect on recruitment or retention. MMIs are a useful tool for trial recruitment in children and young people, and they could reduce trial recruitment periods.

Psychometric Properties of the Iranian Version of Contrast Avoidance Questionnaires: Could Contrast Avoidance Be a New Transdiagnostic Construct?

The contrast avoidance model (CAM) hypothesizes that individuals with chronic worry recruit worry to create and maintain a negative emotional state to avoid sudden increases in negative emotions. Preliminary evidence using the contrast avoidance questionnaires (CAQs) suggests that there might be a similar mechanism across mood and other anxiety disorders. To continue to assess the CAQs, they should be adapted for other languages and evaluated across multiple symptom domains. The present study aimed to develop the Persian versions of the CAQs and examine the transdiagnostic nature of CAM across two studies. A large Persian-speaking college student sample (Total n = 1438) was used to evaluate the factor structure of the CAQs (Study 1) and the psychometric properties of CAQs (Study 2). Results supported the two-factor structure of the CAQ-W (worry) and CAQ-GE (general emotion). Results showed that CAQ-W was a significant predictor of anxiety-related measures. However, CAQ-GE and IUS-12 significantly predicted depressive and other symptoms over the CAQ-W. Results demonstrated excellent psychometric properties. They indicate that contrast avoidance, measured via CAQ-GE, could be a transdiagnostic construct, and CAQ-W may be more sensitive to anxiety-specific contrast avoidance among Persian speaking and/or Iranian individuals.

Coping in the Clinic: Effects of Clinically Elevated Anxiety on Dynamic Neurophysiological Mechanisms of Escape/Avoidance Preparation.

BACKGROUND: Treatments for anxiety and related disorders target exaggerated escape/avoidance as a core feature, but current methods fail to improve escape/avoidance habits for many treatment-seeking individuals. To support developing tools that increase treatment efficacy by targeting mechanisms more directly, the current work examined potential distinctions in the neurophysiologies of escape and avoidance and tested how clinical anxiety affects these neurophysiologies. METHODS: Twenty-five treatment-seeking individuals with varied principal diagnoses (e.g., generalized anxiety disorder, posttraumatic stress disorder) and 20 non-treatment-seeking control subjects participated. In the study task, approximately 5.25-second cues predicted aversive images that could be avoided (blocked by a button press before image onset), escaped (ended by a button press after image onset), or not controlled. To examine neural processing and defensive response modulation, anticipatory event-related potentials were derived, and startle reflexes were probed throughout each cue. RESULTS: Multidimensional profiles were observed such that 1) anticipatory event-related potential enhancement was only reliable during avoidance preparation, and event-related potentials potentially reflected perceived/instrumental control; and 2) startle reflexes were inhibited during avoidance preparation, relatively enhanced during escape preparation, and further enhanced during uncontrollable anticipation, thus potentially reflecting fear-related activation. Treatment-seeking status, then, did not affect cortical processing, but it did moderate context-dependent fear (if individuals with severe depression were excluded) such that treatment-seeking individuals without depression showed exaggerated startle during escape, but not avoidance, preparation. CONCLUSIONS: Data suggest a specific effect of anxiety on fear system activation during preparation to escape aversion. This effect warrants further investigation as a precision target for interventions that directly modulate the specific underlying neural circuitry.

The influence of self-focused attention on emotional picture processing: An ERP study.

Research has documented neurophysiological indicators of anticipation (Stimulus Preceding Negativity [SPN]) and perception (Late Positive Potential [LPP]) of threat, yet little is known as to how self-focused attention manipulations influence emotion processing within the context of cued picture viewing. With self-referent attention moderating attention to external stimuli, it is necessary to document how self-focused attention impacts attention and the ability to emotionally process external threat. The goal of the present study was to evaluate the impact of self-focused attention on the anticipation and perceptual processing of unpleasant pictures within a cued-picture viewing paradigm among 33 participants. Overall, the results suggest that the self-focused attention manipulations disrupted anticipation but not processing of pictures, as indexed by the SPN and LPP respectively. Self-focused attention appears to disrupt the preparatory attention for upcoming unpleasant stimuli, potentially through loading cognitive resources or activation of associative defensive responding. Collectively, these findings demonstrate the impact of self-focused attention within the context of emotional picture processing and suggest further areas of investigation.

Pre-Existing Medical Conditions: A Systematic Literature Review of a Silent Contributor to Adult Drowning.

Medical conditions can increase drowning risk. No prior study has systematically reviewed the published evidence globally regarding medical conditions and drowning risk for adults. MEDLINE (Ovid), PubMed, EMBASE, Scopus, PsycINFO (ProQuest) and SPORTDiscus databases were searched for original research published between 1 January 2005 and 31 October 2021 that reported adult (≥15 years) fatal or non-fatal drowning of all intents and pre-existing medical conditions. Conditions were grouped into the relevant International Classifications of Diseases (ICD) codes. Eighty-three studies were included (85.5% high-income countries; 38.6% East Asia and Pacific region; 75.9% evidence level III-3). Diseases of the nervous system (n = 32 studies; 38.6%), mental and behavioural conditions (n = 31; 37.3%) and diseases of the circulatory system (n = 25; 30.1%) were the most common categories of conditions. Epilepsy was found to increase the relative risk of drowning by 3.8 to 82 times, with suggested preventive approaches regarding supervised bathing or showering. Drowning is a common suicide method for those with schizophrenia, psychotic disorders and dementia. Review findings indicate people with pre-existing medical conditions drown, yet relatively few studies have documented the risk. There is a need for further population-level research to more accurately quantify drowning risk for pre-existing medical conditions in adults, as well as implementing and evaluating population-level attributable risk and prevention strategies.

Chronic rectal anastomosis complications prior to ileostomy reversal: development of a pilot classification system and associated outcomes.

BACKGROUNDS: A loop ileostomy may reduce the severity of acute anastomotic complications after low rectal resection, but some patients have persistent rectal anastomotic problems. No consensus exists for the management of patients with a chronic low rectal anastomosis complication and a loop ileostomy. There is need for a standard description of these anastomotic complications and to determine whether it is safe to reverse the ileostomy. This study proposes a classification of chronic rectal anastomotic complications and to report the correlation with successful restoration of rectal continuity. METHODS: This was a retrospective project from a prospectively maintained database at a single colorectal unit in a large tertiary hospital in Metropolitan Melbourne. Patients with rectal anastomotic complications following rectal cancer resections between March 2012 and October 2019 were included. A classification of chronic rectal anastomotic complication was developed by reviewing the interval assessments of the rectal anastomosis. The classification categories were correlated with outcomes after stoma closure. RESULTS: Of the 149 patients, 20 patients had an anastomotic complication identified during work up prior to loop ileostomy reversal. Eleven patients had an anastomotic stenosis and nine had an anastomotic defect. Eighteen patients were eligible for stomal closure. The majority (11/12) of patients with a Type 1 stenosis or defect had no rectal complications after stoma closure. CONCLUSION: The classification system helps to describe chronic rectal anastomotic abnormalities and guide management. Although these patients may be a challenge, many can undergo successful ileostomy reversal.

A vulnerable residential environment is associated with higher risk of mortality and early transition to permanent residential aged care for community dwelling older South Australians.

OBJECTIVES: This study examined the impact of the residential environment, measured by the Healthy Ageing/Vulnerable ENvironment (HAVEN) Index, on risk of mortality or entry into Permanent Residential Aged Care (PRAC). DESIGN: A retrospective cohort study using data from the Registry of Senior Australians (ROSA) was conducted. HAVEN Index values were matched to the ROSA by residential postcode. STUDY SETTING AND PARTICIPANTS: Older individuals living in metropolitan Adelaide and receiving their first eligibility assessment for aged care services between 2014 and 2016 (N = 16,944). MAIN OUTCOME MEASURE: Time to death and entry into PRAC were the main outcomes. RESULTS: A higher HAVEN Index value, which represents a favourable residential environment, was associated with a lower risk of mortality and delayed entry to PRAC. For every 0.1 unit increase in HAVEN Index value, the risk of mortality is 3% lower (adjusted hazard ratio [HR], 95% confidence interval [CI] = 0.97, 0.96-0.99) and the risk of entry to PRAC is 5% lower (adjusted subdistribution HR, 95%CI = 0.95, 0.94-0.97) in the first 2 years following aged care assessment. After 2 years, the HAVEN Index was not associated with the risk of transition to PRAC. CONCLUSION: Place-based health inequalities were identified in Australians seeking aged care services, demonstrating that a better understanding of local neighbourhoods may provide insight into addressing ageing inequalities. Spatial indexes, such as the HAVEN Index, are useful tools to identify areas where populations are more vulnerable to adverse health outcomes, informing responses to prioritise local improvements and health interventions to enable healthy ageing.

Documenting the late positive potential towards self-imagery within social anxiety.

Models of social anxiety propose that negative self-imagery is a maintenance factor of psychopathology, yet the mechanisms of this relationship are unclear. One proposed mechanism is attention towards self-images. However, self-image creation does not occur in isolation and is likely influenced by other mechanisms, such as anticipatory processing (AP). The current study aimed to investigate how trait social anxiety and AP influence motivated attention during self-imagery (i.e., late-positive potential; LPP). Participants (N = 40) with a mean age of 18.95 (SD = 1.22) completed AP manipulations and a self-imagery task. Results revealed that participants with high levels of social anxiety who engaged in AP demonstrated blunted LPP activity in the late time window (6000-10,000 ms) relative to those who engaged in Distraction. These results suggest that motivated attention towards self-imagery may be impacted by anticipatory processing, but less influenced by the valence of self-imagery. Given previous research has been limited in methodology, this study expands upon current research by documenting the neural mechanisms of self-imagery manipulations within social anxiety.

Independent Psychometric Evaluation and Predictive Utility of The Social Anxiety Questionnaire.

The Social Anxiety Questionnaire (SAQ) is a 10-item measure of social anxiety developed to comprehensively and concisely target the mechanisms described in Clark and Wells' model of social anxiety and address the breadth of social anxiety symptoms which may not all be encompassed in existing questionnaires. The aim of the current studies is to independently investigate the factor structure of the SAQ (i.e., Study 1 and 2) and determine its predictive validity and utility (i.e., Study 3 and 4). Data were collected across 4 studies to evaluate the factor structure and utility. Overall, the results suggest that a total summed score of the SAQ appeared to capture unique aspects of social anxiety that may not be captured using a single measure and appears to provide utility in experimental manipulations of theoretical maintenance factors. The current study was limited by a convenience sample and future research should continue to document the psychometric properties and clinical utility of this novel measure of social anxiety. The SAQ may show promise in both correlational and experimental research but future research should consider further evaluation of its utility.

Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.

Evaluation of Uroflowmetry Curve Patterns and Nomogram Construct in Healthy Nulliparous Female Adults.

OBJECTIVE: The aims of the study were to construct uroflowmetry nomograms, evaluate uroflowmetry flow rate patterns, and graphically illustrate overlaid uroflowmetry curves in nulliparous female adult volunteers. METHODS: We performed a prospective cross-sectional study evaluating uroflowmetry curve and flow rate patterns on a cohort of nulliparous female adult volunteers. Primary outcome was construction of uroflowmetry maximum and average flow rate nomograms. Secondary outcomes included evaluation of uroflowmetry flow rate patterns and graphical illustrations of overlaid uroflowmetry curves. Uroflowmetry printouts were overlaid and used to create a model of uroflow patterns, and nomogram curves were analyzed in 5 groups based on voided volumes. RESULTS: We enrolled 164 participants and 158 had voided volumes between 50 mL and 800 mL. Participants' mean age and body mass index were 25 years and 23, respectively. Maximum and average flow rate nomograms were created, and analysis of uroflow parameters was performed. Median voided volume was 241 mL (149-431 mL), the median maximum flow was 29 mL/s (20-38 mL/s), and the median average flow was 15 mL/s (10-19 mL/s). Participants were divided into 5 groups based on voided volumes. The nomogram patterns for each voided volume group were visually different from typical nomogram patterns. CONCLUSIONS: Uroflowmetry curves and flow rates vary significantly according to voided volume. Our study suggests that in normal healthy nulliparous female adults there is likely a broader range of normal flow rates and uroflowmetry curves than what has been previously reported. Further research is needed to investigate the accuracy of these finding.

Topically delivered 22 nt siRNAs enhance RNAi silencing of endogenous genes in two species.

MAIN CONCLUSION: 22 nt siRNAs applied to leaves induce production of transitive sRNAs for targeted genes and can enhance local silencing. Systemic silencing was only observed for a GFP transgene. RNA interference (RNAi) is a gene silencing mechanism important in regulating gene expression during plant development, response to the environment and defense. Better understanding of the molecular mechanisms of this pathway may lead to future strategies to improve crop traits of value. An abrasion method to deliver siRNAs into leaf cells of intact plants was used to investigate the activities of 21 and 22 nt siRNAs in silencing genes in Nicotiana benthamiana and Amaranthus cruentus. We confirmed that both 21 and 22 nt siRNAs were able to silence a green fluorescent protein (GFP) transgene in treated leaves of N. benthamiana, but systemic silencing of GFP occurred only when the guide strand contained 22 nt. Silencing in the treated leaves of N. benthamiana was demonstrated for three endogenous genes: magnesium cheletase subunit I (CHL-I), magnesium cheletase subunit H (CHL-H), and GENOMES UNCOUPLED4 (GUN4). However, systemic silencing of these endogenous genes was not observed. Very high levels of transitive siRNAs were produced for GFP in response to treatment with 22 nt siRNAs but only low levels were produced in response to a 21 nt siRNA. The endogenous genes tested also produced transitive siRNAs in response to 22 nt siRNAs. 22 nt siRNAs produced greater local silencing phenotypes than 21 nt siRNAs for three of the genes. These special properties of 22 nt siRNAs were also observed for the CHL-H gene in A. cruentus. These experiments suggest a functional role for transitive siRNAs in amplifying the RNAi response.