International students' perspectives on medical school and internship: 'Oh international? Are you international?'

BACKGROUND: International students account for a significant proportion of medical graduates Australia-wide, and most opting to remain in Australia for their first year of practice (Internship). Hence, understanding this particular demographic's perspectives is crucial for curriculum and workforce planning. Despite this, very few studies have addressed this demographic, and none have explored the impact of the COVID-19 pandemic on international medical students specifically. AIM: A qualitative design was used to explore the perspectives of final-year international medical students at an Australian medical school as they prepared for transition to internship during the COVID-19 pandemic. METHODS: Participants engaged in a semi-structured interview about the pandemic's personal and professional implications. The data were analysed using inductive thematic analysis. RESULTS: Seven out of 34 final-year international medical students at the University of Adelaide participated. The main themes identified were that isolation was magnified, institutional support was lacking and that uncertainty was challenging. The pandemic did not deter participants from pursuing an Australian internship, as Australia was considered a desirable place for internship compared to their home countries. CONCLUSIONS: While the COVID-19 pandemic exacerbated the situation, many of the challenges identified by international students already existed. Issues such as social isolation, racial discrimination, financial hardship and lack of institutional support have been prevalent for decades. Insights from this study reveal a need to improve the medical school experience. Australian Universities have a responsibility to ensure fair treatment of international students by training faculty, implementing support programmes and ensuring an inclusive and culturally safe learning environment.

A novel 4'-brominated derivative of fisetin induces cell cycle arrest and apoptosis and inhibits EGFR/ERK1/2/STAT3 pathways in non-small-cell lung cancer without any adverse effects in mice.

The therapeutic toxicity and resistance to currently available treatment options are major clinical challenges for the management of lung cancer. As a novel strategy, we synthesized analogues of a known flavonol, fisetin, which has shown anti-tumorigenic potential against cancer in cell culture with no adverse effects in animal models. We studied the synthetic analogues of fisetin for their anti-cancer potential against lung cancer cells, toxicity in mice and efficacy in a xenograft model. Brominated fisetin analogues were screened for their effects on the viability of A549 and H1299 lung cancer cells, and three analogues (3a, 3b, 3c), showed improved activity compared to fisetin. These analogues were more effective in restricting lung cancer cell proliferation, inducing G2 M phase cell cycle arrest and apoptosis. The fisetin analogues also downregulated EGFR/ERK1/2/STAT3 pathways. Fisetin analogue-induced apoptosis was accompanied by a higher Bax to Bcl-2 expression ratio. Based on the in vitro studies, the most effective fisetin analogue 3b was evaluated for in vivo toxicity, wherein it did not show any hepatotoxicity or adverse health effects in mice. Furthermore, analogue 3b showed greater antitumor efficacy (p < .001) as compared to its parent compound fisetin in a human lung cancer cell xenograft study in athymic mice. Together, our data suggest that the novel fisetin analogue 3b is more effective in restricting lung cancer cell growth, both in vitro as well as in vivo, without any apparent toxicity, supporting its further development as a novel anti-lung cancer agent.

Foster Caregivers' Perceptions of Children's Sleep Patterns, Problems, and Environments.

OBJECTIVE: The disparity of problems, impairments, and disorders among children in foster care is well-documented and spans virtually every domain of functioning. Sleep, however, has received minimal attention among this vulnerable group, which is concerning given the multitude of ways sleep affects children's development, health, and behavior. METHODS: A total of 485 foster caregivers from across the United States completed a survey including quantitative items and qualitative, open-ended questions about sleep and related health and behavior for one child (M = 6.4 years, SD = 2.2; range 4-11 years) currently in their care. RESULTS: Overall, caregivers reported developmentally appropriate child sleep and wake times; however, difficulty falling asleep (avg. 46 min per night) and staying asleep (avg. 34 min awake overnight) were common. Additionally, a high prevalence of sleep-related problems was reported including moving to someone else's bed during the night (85.8%), nightmares (51.2%), sleep terrors (26.4%), snoring (32.8%), bedwetting (31.6%), and teeth grinding (21.8%). Qualitative responses indicated emotional and behavioral challenges at bedtime, particularly elevated fear, and anxiety. CONCLUSIONS: Findings are consistent with previous work finding significant health disparities among children placed in foster care. Results highlight a need for trauma-informed, behavioral sleep interventions for this pediatric population which might serve to reduce other health disparities.

Ultra-high-performance supercritical fluid chromatography-mass spectrometry for the analysis of organic contaminants in sediments.

A nontarget screening method was developed based on D-optimal designs for ultra-high performance supercritical fluid chromatography with positive and negative electrospray ionization mode mass spectrometry. A mixture of organic contaminants such as pesticides, steroids, surfactants, phenolic and fatty acids, and polycyclic aromatic hydrocarbon derivatives, was used for the optimization. An aprotic mixture of dichloromethane and acetone [3:1] performed overall best as the injection solvent. The highest peak capacities (n) were accomplished at the shallowest gradient (1%B/min), ammonium formate (n = 378 in negative ionization mode), or ammonium acetate (n = 327 in positive ionization mode) in methanol as the modifier. Capillary voltage, make-up solvent flow rate, water, and additive concentration were the most significant factors for improving peak intensity: higher peak intensities were obtained at lower additive concentrations (5mM ammonium formate), and with 5% water in positive ionization mode. Conversely, water had detrimental effects in negative ionization mode. The optimized method was used to quantify organic contaminants in 17 freshwater sediment samples from Copenhagen, Denmark. Out of 50 monitored contaminants, 35 were detected in at least one sample. Further, the method has a potential for target and nontarget screening analysis of organic contaminants in solid matrices.

Evaluating an inquiry-based learning program.

Inquiry-based learning (IBL) is a promising educational framework that is understudied in graduate medical education. To determine participant satisfaction and engagement with phases of an IBL postgraduate education program, a mixed-methods study collected data via survey statements and open-ended responses. The authors included participants attending an intensive care medicine (ICM) IBL program from May to November 2020. Quantitative outcomes included participants' satisfaction with the IBL format and impact of engagement with IBL on the learning experience. Qualitative outcomes explored determinants of engagement with IBL phases and the impact on the learning experience. Of 378 attendees, 167 submitted survey responses (44.2%). There was strong agreement relating to overall satisfaction (93.4%). Responses indicated engagement with "orientation" (94.6%), "conceptualization" (97.3%), "discussion" (91.1%), and "conclusion" (91.0%) but limited engagement with the "investigation" phase (48.1%). Greater engagement with IBL phases had positive impacts, with repeat attenders having clearer learning objectives (79.1% vs. 56.6%, P < 0.05) and enhanced learning through collaborative discussion (65.9% vs. 48.7%, P < 0.05). Qualitative analysis showed that ICM learners value active learning principles, clear objectives, and a safe environment to expand their "knowledge base." Sessions facilitated "clinically relevant learning," with application of theoretical knowledge. Learners transformed and "reframed their understanding," using the input of others' experiences. ICM learners were highly satisfied with the IBL format and reported valuable learning. Participants engaged strongly with all IBL phases except the investigation phase during the sessions. IBL facilitated learners' active construction of meaning, facilitating a constructivist approach to learning.NEW & NOTEWORTHY An inquiry-based learning (IBL) program was launched as part of a novel binational intensive care medicine education program. Postgraduate intensive care medicine practitioners participated in this education intervention, where facilitated group discussions explored core intensive care medicine concepts. Survey responses indicated overall satisfaction, engagement with the IBL format, and a constructivist approach to learning. This study provided new insights into the benefits and challenges of an IBL program in the context of practicing clinicians.

Parental-leave policies and perceptions of pregnancy during surgical residency training in North America: a scoping review.

BACKGROUND: The number of surgical residents experiencing childbearing during residency training is increasing, and there is an absence of clarity with respect to parental-leave, lactation and return-to-work policies in support of residents. The aim of this review was to examine parental-leave policies during residency training in surgery and the perceptions of these policies by residents, program directors and coresidents, as described in the literature. METHODS: We performed a scoping review of the literature based on the following themes: maternity or parental-leave policies; antepartum work-restriction policies and obstetric complications; accommodations for training absences; support for, and perceptions of, maternity or parental leave during residency training; and challenges upon return to work, namely resident performance and breastfeeding. RESULTS: Parental-leave policies during surgical residency training have historically lacked clarity and enforcement. Although recommendations for parental leave are now in place, this may have historically contributed to a lack of perceived support for surgical residents and may result in variable leave permitted to residents. Unclear policies may also contribute to career dissatisfaction among resident parents, which may deter qualified individuals from selecting surgical subspecialties. CONCLUSION: A call for a cultural shift is required to inform policies that would better support residents across all surgical specialties to pursue success in their dual roles as parents and surgeons. With increased awareness, progress in policy and guideline development is under way.

Sensation Seeking in Children and Adults with Pediatric-Onset Bipolar Disorder.

Bipolar disorder (BD) is one of the most impairing psychiatric illnesses. Those with pediatric-onset BD tend to have worse outcomes; therefore, accurate conceptualization is important for aspects of care, such as tailored treatment interventions. Sensation seeking behaviors may be a window into the psychopathology of pediatric-onset BD. Participants with BD and healthy controls (HC) ages 7-27 completed self-report assessments, including the Sensation Seeking Scale- V (SSS-V). Among the BD group, there was a significant positive correlation between the Disinhibition subscale and age. Analyses indicated that the BD group scored lower on the Thrill and Adventure Seeking subscale but higher on the Disinhibition scale when compared to the HC group. We found that individuals with pediatric-onset BD are more likely to engage in socially risky behaviors. These results are an important step in understanding sensation seeking characteristics in BD youth and improving treatment, ultimately helping individuals live a more stable life.

The ACCELERATE Plus (assessment and communication excellence for safe patient outcomes) Trial Protocol: a stepped-wedge cluster randomised trial, cost-benefit analysis, and process evaluation.

BACKGROUND: Nurses play an essential role in patient safety. Inadequate nursing physical assessment and communication in handover practices are associated with increased patient deterioration, falls and pressure injuries. Despite internationally implemented rapid response systems, falls and pressure injury reduction strategies, and recommendations to conduct clinical handovers at patients' bedside, adverse events persist. This trial aims to evaluate the effectiveness, implementation, and cost-benefit of an externally facilitated, nurse-led intervention delivered at the ward level for core physical assessment, structured patient-centred bedside handover and improved multidisciplinary communication. We hypothesise the trial will reduce medical emergency team calls, unplanned intensive care unit admissions, falls and pressure injuries. METHODS: A stepped-wedge cluster randomised trial will be conducted over 52 weeks. The intervention consists of a nursing core physical assessment, structured patient-centred bedside handover and improved multidisciplinary communication and will be implemented in 24 wards across eight hospitals. The intervention will use theoretically informed implementation strategies for changing clinician behaviour, consisting of: nursing executive site engagement; a train-the-trainer model for cascading facilitation; embedded site leads; nursing unit manager leadership training; nursing and medical ward-level clinical champions; ward nurses' education workshops; intervention tailoring; and reminders. The primary outcome will be a composite measure of medical emergency team calls (rapid response calls and 'Code Blue' calls), unplanned intensive care unit admissions, in-hospital falls and hospital-acquired pressure injuries; these measures individually will also form secondary outcomes. Other secondary outcomes are: i) patient-reported experience measures of receiving safe and patient-centred care, ii) nurses' perceptions of barriers to physical assessment, readiness to change, and staff engagement, and iii) nurses' and medical officers' perceptions of safety culture and interprofessional collaboration. Primary outcome data will be collected for the trial duration, and secondary outcome surveys will be collected prior to each step and at trial conclusion. A cost-benefit analysis and post-trial process evaluation will also be undertaken. DISCUSSION: If effective, this intervention has the potential to improve nursing care, reduce patient harm and improve patient outcomes. The evidence-based implementation strategy has been designed to be embedded within existing hospital workforces; if cost-effective, it will be readily translatable to other hospitals nationally. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ID: ACTRN12622000155796. Date registered: 31/01/2022.

Access to eye care during the COVID-19 pandemic, India.

OBJECTIVE: To study the impact of the coronavirus disease 2019 (COVID-19) pandemic on outpatient visits to eye care facilities in south India. METHODS: We used data on 7.69 million outpatient visits to primary (i.e. vision centres), secondary and tertiary Aravind Eye Care System's centres between January 2019 and June 2021. We compared outpatient numbers and outpatients' age and sex between the pandemic period and the pre-pandemic period in 2019 for all centres, whereas vision and ophthalmic assessments were compared for vision centres only. FINDINGS: During the first wave, the number of outpatient visits at tertiary, secondary and vison centres was 39% (647 968/1 656 296), 60% (170 934/283 176) and 73% (180 502/246 282) respectively, of 2019 levels. During the second wave, outpatient visits at tertiary, secondary and vision centres were 54% (385 092/710 949), 73% (88 383/121 739) and 79% (121 993/154 007), respectively, of 2019 levels. The proportion of outpatients who were female or younger than 20 years or older than 60 years was significantly lower during the first and second waves than in 2019 (P < 0.0001 for all). The proportion of outpatients whose worse eye vision was poorer than 5/60 or who required referral was significantly higher (P < 0.0001 for both). CONCLUSION: Restrictive measurements led to declines in outpatient visits, however the decline was less at secondary and vision centres than at tertiary centres. Easy access to specialized ophthalmic care via telemedicine and the relative proximity of these centres to communities helped reduce barriers to access.

Placental mitochondria adapt developmentally and in response to hypoxia to support fetal growth.

Mitochondria respond to a range of stimuli and function in energy production and redox homeostasis. However, little is known about the developmental and environmental control of mitochondria in the placenta, an organ vital for fetal growth and pregnancy maintenance in eutherian mammals. Using respirometry and molecular analyses, the present study examined mitochondrial function in the distinct transport and endocrine zones of the mouse placenta during normal pregnancy and maternal inhalation hypoxia. The data show that mitochondria of the two zones adopt different strategies in modulating their respiration, substrate use, biogenesis, density, and efficiency to best support the growth and energy demands of fetoplacental tissues during late gestation in both normal and hypoxic conditions. The findings have important implications for environmentally induced adaptations in mitochondrial function in other tissues and for compromised human pregnancy in which hypoxia and alterations in placental mitochondrial function are associated with poor outcomes like fetal growth restriction.

Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11.

PURPOSE: Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. METHODS: We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. RESULTS: Patients with variants in GDF11 presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients' variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants in our cohort are partial LOF variants. CONCLUSION: GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.

Differences in Sociodemographic Disparities Between Patients Undergoing Surgery for Advanced Colorectal or Ovarian Cancer.

BACKGROUND: Cytoreductive surgery (CRS) for ovarian cancer with peritoneal metastases (OPM) is an established treatment, yet access-related racial and socioeconomic disparities are well documented. CRS for colorectal cancer with peritoneal metastases (CRPM) is garnering more widespread acceptance, and it is unknown what disparities exist with regards to access. METHODS: This retrospective cross-sectional multicenter study analyzed medical records from the National Cancer Database from 2010 to 2015. Patients diagnosed with CRPM or ORP only and either no or confirmed resection were included. Patient- and facility-level characteristics were analyzed using uni- and multivariable logistic regressions to identify associations with receipt of CRS. RESULTS: A total of 6634 patients diagnosed with CRPM and 14,474 diagnosed with OPM were included in this study. Among patients with CRPM, 18.1% underwent CRS. On multivariable analysis, female gender (odds ratio [95% CI] 2.04 [1.77-2.35]; P < 0.001) and treatment at an academic or research facility (OR 1.55 [1.17-2.05]; P = 0.002) were associated with CRS. Among patients with OPM, 87.1% underwent CRS. On multivariable analysis, treatment at facilities with higher-income patient populations was positively associated with CRS, while age (OR 0.97 [0.96-0.98]; P < .0001), use of nonprivate insurance (OR 0.69 [0.56-0.85]; P = 0.001), and listed as Black (OR 0.62 [0.45-0.86]; P = 0.004) were negatively associated with CRS. CONCLUSION: There were more systemic barriers to CRS for patients with OPM than for patients with CRPM. As CRS becomes more widely practiced for CRPM, it is likely that more socioeconomic and demographic barriers will be elucidated.

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Latent class analysis of bipolar disorder symptoms and suicidal ideation and behaviors.

Individuals with bipolar disorder are at increased risk of dying by suicide compared to healthy controls and those with unipolar depression. Previous studies show that depressive symptoms and mixed episodes of mania and depression are related to suicide. However, most of these studies adopt a variable-centered approach to understanding how specific symptoms relate to suicidal ideation, without addressing how these symptoms and symptom profiles relate to suicidal behaviors. OBJECTIVES: Using latent class analysis, this study adopts a person-centered approach to examine whether subtypes of patients with bipolar disorder differ in their levels of suicidal ideation and behaviors. METHODS: A total of 150 patients from a behavioral health outpatient clinic were recruited. Latent classes were generated based on self reports of their depressive and manic symptoms. RESULTS: Five classes of patients with bipolar disorder were identified, namely, a minimal symptom, mania, moderately depressed, severely depressed, and mixed depression-mania subtypes. Those in the severely depressed and mixed depression-mania groups reported significantly higher levels of suicidal ideation and behaviors compared to the other groups. CONCLUSIONS: Our findings provide further support for the strong relationship between depressive symptoms and suicidality. These findings are significant as they shed light on the different suicide risk profiles among a heterogenous group of patients with bipolar disorder. Name of clinical trial: Suicidal Behavior in Patients Diagnosed with Bipolar Disorder: The Roles of Biological and Childhood and Adult Environmental Risk Factors. ClinicalTrials.gov Identifier: NCT02604277.

The influence of chest X-ray results on antibiotic prescription for childhood pneumonia in the emergency department.

The aim of this study is to evaluate the influence of chest X-ray (CXR) results on antibiotic prescription in children suspected of lower respiratory tract infections (RTI) in the emergency department (ED). We performed a secondary analysis of a stepped-wedge, cluster randomized trial of children aged 1 month to 5 years with fever and cough/dyspnoea in 8 EDs in the Netherlands (2016-2018), including a 1-week follow-up. We analysed the observational data of the pre-intervention period, using multivariable logistic regression to evaluate the influence of CXR result on antibiotic prescription. We included 597 children (median age 17 months [IQR 9-30, 61% male). CXR was performed in 109/597 (18%) of children (range across hospitals 9 to 50%); 52/109 (48%) showed focal infiltrates. Children who underwent CXR were more likely to receive antibiotics, also when adjusted for clinical signs and symptoms, hospital and CXR result (OR 7.25 [95% CI 2.48-21.2]). Abnormalities on CXR were not significantly associated with antibiotic prescription.Conclusion: Performance of CXR was independently associated with more antibiotic prescription, regardless of its results. The limited influence of CXR results on antibiotic prescription highlights the inferior role of CXR on treatment decisions for suspected lower RTI in the ED. What is Known: • Chest X-ray (CXR) has a high inter-observer variability and cannot distinguish between bacterial or viral pneumonia. • Current guidelines recommend against routine use of CXR in children with uncomplicated respiratory tract infections (RTIs) in the outpatient setting. What is New: • CXR is still frequently performed in non-complex children suspected of lower RTIs in the emergency department • CXR performance was independently associated with more antibiotic prescriptions, regardless of its results, highlighting the inferior role of chest X-rays in treatment decisions.

Comparison of Afirma Gene Expression Classifier with Gene Sequencing Classifier in indeterminate thyroid nodules: A single-institutional experience.

INTRODUCTION: The Afirma test has been used in the diagnosis of cytologically indeterminate thyroid nodules to reduce diagnostic uncertainty and unnecessary surgeries. Gene Sequencing Classifier (GSC) was developed to improve the positive predictive value and overall test performance of Gene Expression Classifier (GEC). Here we present our experience comparing the performance of first-generation assay of Afirma (GEC) with the new assay (GSC). METHODS: Retrospective analysis was performed on all Bethesda III and IV cytology thyroid nodules tested with GEC and GSC. Test performance was evaluated by surgical pathology outcomes. RESULTS: In total, 167 cases were tested with GEC, of which 49% were reported as benign. Fourteen cases had surgical follow-up with 11 benign, one non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and two malignant diagnoses. Of the 167 cases, 51% had suspicious GEC result. Fifty-seven of these suspicious GEC cases had surgical follow-up with 28 benign, nine NIFTP and 20 malignant histology. There 133 cases tested with GSC, of which 61% were reported as benign. Ten cases had surgical follow-up, all of which showed benign results and 32% of the cases were tested as suspicious. Thirty-six cases with suspicious GSC had surgical follow-up. Fourteen of them had benign, five NIFTP, and 17 malignant surgical pathology. Based on molecular testing, surgical resection could have been be prevented 61% with GSC, compared to 49% with GEC test. CONCLUSION: Our experience shows that GSC has a better test performance than GEC. Also, our data support that GSC identify more cases as benign and reduces the number of unnecessary surgeries compared to GEC.

Evaluation of a clinical decision rule to guide antibiotic prescription in children with suspected lower respiratory tract infection in The Netherlands: A stepped-wedge cluster randomised trial.

BACKGROUND: Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule. METHODS AND FINDINGS: In a stepped-wedge cluster randomised trial, we included children aged 1-60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power of our study. CONCLUSIONS: In this multicentre ED study, we observed that a clinical decision rule for childhood pneumonia did not reduce overall antibiotic prescription, but that it was non-inferior to usual care. Exploratory analyses showed fewer strategy failures and that fewer antibiotics were prescribed in low/intermediate-risk children, suggesting improved targeting of antibiotics by the decision rule. TRIAL REGISTRATION: Netherlands Trial Register NTR5326.

Wearable electromyography recordings during daily life activities in children with cerebral palsy.

AIM: To test whether wearable textile electromyography (EMG) recording systems may detect differences in muscle activity levels during daily activities between children with cerebral palsy (CP) and age-matched typically developing children. METHOD: Wearable textile EMG recording systems were used to obtain leg muscle activity in 10 children with spastic CP (four females, six males; mean age 9y 6mo, standard deviation [SD] 2y 4mo, range: 6-13y; Gross Motor Function Classification System [GMFCS] level I and II) and 11 typically developing children (four females, seven males; mean age 9y 9mo, SD 1y 11mo, 7-12y) at rest and while performing seven daily activities. RESULTS: Children with CP showed significantly lower absolute EMG levels during maximal voluntary contractions (MVCs) of muscles on the most affected side as compared to the least affected side and to typically developing children. None of the typically developing children or children with CP showed detectable EMG activity in resting situations. EMG activity relative to MVC was greater in children with CP during walking, jumping, and kicking on the most affected side as compared to the least affected side and to typically developing children. INTERPRETATION: Wearable textile EMG recording systems may be used to determine differences in muscle activity during daily activities in children with CP. Children with CP showed reduced muscle activity during daily activities compared to their peers, but used a significantly larger part of their maximal voluntary muscle strength to perform these activities. WHAT THIS PAPER ADDS: Wearable textile electromyography (EMG) systems are feasible for measurement of daily muscle activity in children with cerebral palsy (CP). Children with CP showed reduced EMG levels during maximal voluntary contractions. Neither typically developing children or children with CP showed EMG activity in resting situations. Children with CP used a larger part of their voluntary muscle strength during daily activities.

Grabaciones de electromiografía portátil durante las actividades de la vida diaria en niños con parálisis cerebral OBJETIVO: Probar si los sistemas de registro de electromiografía textil portátil (EMG) pueden detectar diferencias en los niveles de actividad muscular durante las actividades diarias entre los niños con parálisis cerebral (PC) y los niños de desarrollo típico de la misma edad. MÉTODO: Se utilizaron sistemas de registro de EMG textiles portátiles para obtener actividad muscular de las piernas en 10 niños con PC espástica (cuatro mujeres, seis varones; edad media 9 años y 6 meses, desviación estándar [ED] 2 años y 4 meses, rango: 6-13 años; Escala de clasificación de función motora gruesa [GMFCS] nivel I y II) y 11 niños típicamente en desarrollo (cuatro mujeres, siete varones; edad media 9 años y 9 meses, DE 1 años y 11 meses, 7-12 años) en reposo y mientras realizan siete actividades diarias. RESULTADOS: Los niños con PC mostraron niveles de EMG absolutos significativamente más bajos durante las contracciones voluntarias máximas (CVM) de los músculos en el lado más afectado en comparación con el lado menos afectado y en los niños con desarrollo típico. Ninguno de los niños con desarrollo típico o niños con PC mostró actividad EMG detectable en situaciones de reposo. La actividad EMG en relación con CVM fue mayor en niños con PC al caminar, saltar y patear en el lado más afectado en comparación con el lado menos afectado y en los niños con desarrollo típico. INTERPRETACIÓN: Los sistemas de registro de EMG textiles portátiles pueden usarse para determinar las diferencias en la actividad muscular durante las actividades diarias en niños con PC. Los niños con PC mostraron una actividad muscular reducida durante las actividades diarias en comparación con sus compañeros, pero utilizaron una parte significativamente mayor de su fuerza muscular voluntaria máxima para realizar estas actividades.

Registros vestíveis de eletromiografia durante atividades de vida diária em crianças com paralisia cerebral OBJETIVO: Testar se registros têxteis vestíveis de eletromiografia (EMG) podem detector diferenças nos níveis de atividade muscular durante atividades de vida diária entre crianças com paralisia cerebral (PC) e crianças com desenvolvimento típico da mesma idade. MÉTODO: Sistemas têxteis vestíveis de EMG foram usados para obter a atividade muscular em 10 crianças com PC espástica (quatro do sexo feminino, seis do sexo masculino; média de idade 9a6m, desvio padrão [DP] 2a 4m, variação: 6-13a; Sistema de Classificação da Função Motora Grossa [GMFCS] nível I e II) e 11 crianças com desenvolvimento típico (quatro do sexo feminino, sete do sexo masculino; média de idade 9a 9m, DP 1a 11m, 7-12a) em repouso e durante a realização de sete atividades de vida diária. RESULTADOS: Crianças com PC mostraram níveis de EMG significativamente menores durante contrações voluntárias máximas (CVMs) de músculos no lado mais afetado, em comparação com o lado menos afetado e com crianças típicas. Nenhuma das crianças típicas ou com PC mostrou atividade de EMG detectável nas situações de repouso. A atividade de EMG relativa a CVM foi maior em crianças com PC durante a marcha, salto e chutes no lado mais afetado em comparação com o lado menos afetado e com crianças típicas. INTERPRETAÇÃO: Sistemas têxteis vestíveis para registro de EMG podem ser usados para determinar diferenças na atividade muscular durante atividades de vida diária em crianças com PC. Crianças com PC mostraram reduzida atividade muscular durante atividades diárias comparadas com seus pares, mas usaram uma porção significativamente maior de sua força voluntária máxima para realizar estas atividades.

Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth.

OBJECTIVE: Recent data show that simvastatin (SIM) and metformin (MET) have anti-proliferative effects in endometrial cancer cells. The combination (MET+SIM) inhibits tumor growth and metastasis in prostate cancer cells which possess similar molecular alterations to many early endometrial cancers. We tested the hypothesis that the anti-proliferative effects of MET+SIM in endometrial cancer cells would be greater than the effects of each agent alone. METHODS: RL95-2, HEC1B, and Ishikawa endometrial cancer cell lines were treated with MET and/or SIM. Growth inhibition was measured by MTS cell proliferation assays. Apoptosis was evaluated by caspase-3, Annexin V, and TUNEL assays and by apoptosis markers (BAX, Bcl-2, Bim) using western blot. Bim was silenced using Bim siRNA to confirm this apoptotic pathway. Treatment effects on the mTOR pathway were investigated by western blot using antibodies to phosphorylated (phospho)-AMPK and phospho-S6. RESULTS: MET+SIM synergistically inhibited growth in all three cell lines. The combination induced apoptosis as measured by TUNEL, Annexin V, and caspase-3 assays. Bim siRNA transfection abrogated this effect-silencing Bim in MET+SIM-treated RL95-2 cells rescued cell viability in MTS assays and reduced caspase-3 activity compared with control siRNA-transfected cells. Combination treatment upregulated phosphorylated AMPK and downregulated downstream phosphorylated S6, suggesting mTOR inhibition as a mechanism for these anti-proliferative effects. CONCLUSIONS: MET+SIM treatment synergistically inhibits endometrial cancer cell viability. This may be mediated by apoptosis and mTOR pathway inhibition. Our results provide preclinical evidence that the combination of these well-tolerated drugs may warrant further clinical investigation for endometrial cancer treatment.

Clinical outcomes in ovarian cancer patients receiving three versus more cycles of chemotherapy after neoadjuvant treatment and interval cytoreductive surgery.

OBJECTIVES: To compare clinical outcomes for stage IIIC and IV ovarian cancer patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery followed by up to three versus more cycles of post-operative chemotherapy. METHODS: We conducted a multi-institution retrospective cohort study of patients treated from January 2005 to February 2016 with neoadjuvant platinum-based therapy followed by interval surgery and post-operative chemotherapy. The following were exclusion criteria: more than four cycles of neoadjuvant chemotherapy, bevacizumab with neoadjuvant chemotherapy, non-platinum therapy, prior chemotherapy, and elevated CA125 values after three post-operative chemotherapy cycles. Progression-free and overall survival and toxicity profiles were compared between groups receiving up to three cycles versus more that three cycles post-operatively. RESULTS: A total of 100 patients met inclusion criteria: 41 received up to three cycles and 59 received more than three cycles. The groups were similar in terms of age, body mass index, performance status, tumor histology, optimal cytoreduction rates, and median number of neoadjuvant chemotherapy cycles. Median progression-free survival was 14 vs 16.6 months in those receiving up to three cycles versus more than three cycles, respectively (HR 0.99, 95% CI 0.58 to 1.68, p=0.97). Similarly, median overall survival was not different at 47.1 vs 69.4 months, respectively (HR 1.96, 95% CI 0.87 to 4.42, p=0.10). There were no differences in grade 2 or higher chemotherapy-related toxicities. CONCLUSIONS: Extending post-operative chemotherapy beyond three cycles in patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery with normalization of CA125 levels was not associated with improved survival or greater toxicity. Future study in a larger cohort is warranted to define optimal length of cytotoxic treatment.