A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial.

BACKGROUND: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. PATIENTS AND METHODS: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. CONCLUSIONS: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

The impact of impulsivity on weight loss after bariatric surgery: a systematic review.

BACKGROUND: Impulsivity has been shown to be associated with obesity through links to pathological eating behavior such as binge eating. The recent literature suggests that impulsivity is linked to poorer outcomes post-bariatric surgery. Impulsivity can be measured in various ways and comprises of three broad domains: impulsive choice, impulsive action, and impulsive personality traits. The aim of this systematic review is to synthesize the current evidence on the impact of impulsivity on post-bariatric surgery weight loss. METHODS: A literature review was performed in February 2020. Original studies investigating the relationship between impulsivity and weight loss post-bariatric surgery were evaluated. RESULTS: Ten studies with a total of 1246 patients were analyzed. There were four case-control, four prospective observational and two retrospective observational studies. The postoperative follow-up ranged from 0.5 to 12 years. Eight studies measuring trait impulsivity did not show any association with weight loss post-bariatric surgery, although two studies reported an indirect effect of impulsivity on weight loss mediated via pathological eating behavior. Assessment of impulsive action by two studies showed that post-bariatric surgery weight loss is affected by impulsive action. CONCLUSION: Impulsivity may adversely affect postoperative outcomes after bariatric surgery. However, this may be specific to state impulsivity or impulsive action rather than trait impulsivity. Patients with a higher state impulsivity may benefit from closer follow-up post-bariatric surgery, as well as cognitive behavioral therapies targeting cognitive control over food. LEVEL OF EVIDENCE: Level I, systematic review.

Isolated fallopian tube torsion in prepubertal females.

Isolated fallopian tube torsion is an uncommon diagnosis. It is particularly rare in the paediatric and post-menopausal age groups. It lacks pathognomonic symptoms, signs and imaging findings, yet each of these diagnostic steps plays a crucial role in early diagnosis. We describe two cases of isolated fallopian tube torsion in prepubertal females.

Distribution of virulence genes in clinical isolates of hospital-associated and community-associated methicillin-susceptible Staphylococcus aureus from Terengganu, Malaysia.

Staphylococcus aureus is a common bacterial pathogen known to cause various kinds of infections due to its repertoire of virulence factors. This study aimed to investigate the distribution of 19 types of virulence genes among clinical isolates of methicillin-susceptible S. aureus (MSSA) using the polymerase chain reaction. A total of 109 MSSA isolates, i.e., 63 hospital-associated (HA) and 46 community-associated (CA) were collected from Hospital Sultanah Nur Zahirah, the main tertiary hospital in Terengganu, Malaysia, from July 2016 to June 2017. The most frequent virulence genes detected were hla (78.9%, n=86) and hld (78.0%, n=85) encoding hemolysins, lukED (56.9%, n=62) encoding leukotoxin ED, followed by seb (26.6%, n=29) and sea (24.8%, n=27) encoding enterotoxins. Among 34 (31.2%) isolates carrying six or more virulence genes, only five were multidrug resistant (MDR) while the remaining isolates were susceptible. Significant associations were discovered between the hld gene with CA-MSSA (p=0.016) and the seo gene with HA-MSSA (p=0.023). However, there is no significant association between virulence genes among the different types of infection. The clinical MSSA isolates in Terengganu showed high prevalence and high diversity of virulence gene carriage.

Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21-p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.

Prospective audit and feedback on antibiotic prescription in an adult hematology-oncology unit in Singapore.

We evaluated the impact of a prospective audit and feedback antimicrobial stewardship program (ASP) on antibiotic prescription and resistance trends in a hematology-oncology unit in a university hospital (National University Cancer Institute, Singapore [NCIS]). A prospective interrupted time-series study comprising 11-month pre-intervention (PIP) and intervention evaluation phases (IEP) flanking a one-month implementation phase was carried out. Outcome measures included defined daily dose per 100 (DDD/100) inpatient-days of ASP-audited and all antibiotics (encompassing audited and non-audited antibiotics), and the incidence-density of antibiotic-resistant microorganisms at the NCIS. Internal and external controls were DDD/100 inpatient-days of paracetamol at the NCIS and DDD/100 inpatient-days of antibiotics prescribed in the rest of the hospital. There were 580 ASP recommendations from 1,276 audits, with a mean monthly compliance of 86.9%. Significant reversal of prescription trends towards reduced prescription of audited (coefficient = -2.621; 95% confidence interval [CI]: -4.923, -0.319; p = 0.026) and all evaluated antibiotics (coefficient = -4.069; 95% CI: -8.075, -0.063; p = 0.046) was observed. No changes were seen for both internal and external controls, except for the reversal of prescription trends for cephalosporins hospital-wide. Antimicrobial resistance did not change over the time period of the study. Adverse outcomes-the majority unavoidable-occurred following 5.5% of accepted ASP recommendations. Safe and effective ASPs can be implemented in the complex setting of hematology-oncology inpatients.

Functional outcome and discharge destination in elderly patients with spinal cord injuries.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To describe functional outcome and discharge destination of elderly patients with traumatic spinal cord injuries. SETTING: National Spinal Injuries Unit, Glasgow, UK. METHODS: We collected data for 5 years on all patients >65 years old with a traumatic spinal cord injury treated at the National Spinal Injuries Unit. RESULTS: We identified 39 patients. Of these, nine patients died during admission; all had cervical spine injuries. The mean age of the 30 survivors was 73 years (range 65-88). The most common cause of injury was a fall: 26 patients (87%). In addition, 21 (70%) sustained injury to cervical cord, 3 (10%) had thoracic and 6 (20%) had lumbar spine fractures. In all, 23 patients (77%) were treated by orthosis and 7 (23%) underwent surgical intervention. Twelve (40%) patients showed an improvement in American Spinal Injury Association impairment scale. The median hospital stay was 136 days. Thus, 11 patients (37%), all with incomplete injuries, were discharged home, 10 (33%) were transferred to nursing homes/community hospitals and 9 patients (30%) were discharged back to the referring hospital, while they were awaiting adjustments at home. Patients who were discharged home had significantly higher Functional Independence Measure scores, both at the onset of rehabilitation and at discharge, than those who were discharged to a nursing home or other hospitals (P<0.01 and <0.001, respectively). DISCUSSION AND CONCLUSION: Although the elderly patients may benefit from the services of a dedicated spinal injuries centre, they should be carefully selected. The patient, relatives as well as the referring doctors should be alerted to the likely long-term outcomes early in the course of the injury. Elderly patients with complete lesions of the spinal cord will almost certainly remain institutionalized. Early endeavour should be made to find alternate rehabilitation settings with a lower-intensity treatment.

Accuracy of parent-reported ages and stages questionnaire in assessing the motor and language skills of preterm infants.

BACKGROUND: Parent-completed tools like the Ages and Stages Questionnaire Third Edition (ASQ-3) are important in developmental screening. As a screening tool, a high negative predictive value (NPV) is critical to avoid missing the diagnosis of developmental delay. This study evaluated the NPV and accuracy of the ASQ-3 in assessing the development of preterm infants. METHODS: Infants born at <32 weeks and/or <1250 grams, presenting to the Neonatal Neurodevelopmental Clinic at the Singapore General Hospital for follow-up from January 2014 to June 2017, at 6, 12, and 18 months corrected age, were included. The ASQ-3 and standardized tests - Peabody Developmental Motor Scale-Second Edition (PDMS-2) and Preschool Language Scale, Fourth Edition UK (PLS-4 UK) - were administered. ASQ-3 gross motor and fine motor scores were compared to PDMS-2 at 6 and 12 months, and ASQ-3 communication scores to PLS-4 UK at 18 months. RESULTS: At 6 months (n = 145), NPV for gross motor and fine motor were 96.4% (accuracy 80.0%) and 95.4% (accuracy 77.2%) respectively. At 12 months (n = 127), NPV for gross motor and fine motor were 88.9% (accuracy 79.8%) and 82.8% (accuracy 74.0%) respectively. At 18 months (n = 113), NPV for language was 56.9% (accuracy 63.7%). CONCLUSIONS: The ASQ-3 showed high NPV and accuracy in screening gross motor and fine motor skills at 6 and 12 months, but not in screening language skills at 18 months. Judicious use of the ASQ-3 may allow for more effective utilization of resources.

Accuracy of radiographer comment following a two-month experiential and blended learning in appendicular skeleton X-ray interpretation: The Singapore experience.

INTRODUCTION: The value of combined blended and experiential learning on radiographer diagnostic comment has not been explored. This study aims to examine the accuracy of image interpretation comment of radiographers who received a period of blended and experiential learning in Radiographer Abnormality Detection Systems (RADS). METHODS: We evaluated the diagnostic opinions of 13 radiographers who received a blended training and experiential learning (a process of self-learning and reflection) in RADS. Radiographers' opinions on 16,483 images were examined using the final radiologists' report as a reference standard. For each radiographer, we recorded the number of true positive, true negative, false positive and false negative opinions and MedCal® was used to calculate diagnostic performance and error rates. A t-test was used to assess whether the number of images read was associated with performance and whether the radiographers retained performance over time. RESULTS: Sensitivity ranged from 87.4 (84.0-90.2) to 98.9 (97.5-99.7) with a mean of 94.3 (93.6-94.8). Specificity varied from 96.4 (94.8-97.5) to 99.9 (99.41-100.0) with a mean of 98.2 (97.9-98.4). Diagnostic accuracy ranged from 93.1 (91.5-94.4) to 99.5 (98.9-99.8) with a mean of 96.9 (96.6-97.1). The mean false positive rate was 0.018 (range: 0.010-0.031) with a false negative rate of 0.057 (range: 0.026-0.11). There were no differences in performance between the first and latter nine months of providing opinions and the number of images reviewed was not associated with performance. CONCLUSION: Radiographers who received blended and experiential learning in RADS provide accurate diagnostic comments on plain emergency appendicular skeleton radiographs. IMPLICATION FOR PRACTICE: A combined blended and experiential learning can equip radiographers to provide diagnostic opinion on plain appendicular skeleton radiographs.

Effect of direct defect closure during laparoscopic inguinal hernia repair ("TEP/TAPP plus" technique) on post-operative outcomes.

PURPOSE: Seroma formation and recurrence in large inguinal hernia still remain an important clinical complication despite decades since the advent of mesh repair. METHODS: In our prospective comparative analysis, we want to evaluate the effect of direct hernia defect closure on surgical outcomes in patients undergoing laparoscopic inguinal hernia repair in two tertiary care institutions in Singapore. The direct hernia defects were closed with non-absorbable sutures incorporating the pseudosac. RESULTS: A group of 241 patients underwent laparoscopic inguinal hernia mesh repair for a total of 378 direct defects from April 2014 to July 2018. Of these patients, 98 (40.6%) patients underwent hernia repair without closure of their direct defect while 143 (59.4%) patients underwent direct defect closure. No significant differences were observed between the two patient populations' demographic information and the mean operative time. A total of 219 direct defects were closed and 159 direct defects were not repaired. Compared to the group that did not undergo direct defect closure, the group that had closure of the direct defects demonstrated a statistically significant reduction in recurrence (4.4% versus 0.9%, p = 0.036) and seroma formation (12.6% versus 6.4%, p = 0.045). CONCLUSION: Direct defect closure has proven to be effective in reducing recurrence and seroma formation post-operatively in patients undergoing laparoscopic inguinal hernia repair. Randomized controlled trials will be required to further evaluate these outcomes.

Early entrapment of fourth ventricle following Pseudomonas meningitis in extreme prematurity: Case report.

Trapped fourth ventricle (TFV) as a complication of post-hemorrhagic hydrocephalus (PHH) is widely reported in the pediatric population with a prior history of ventriculo-peritoneal (VP) shunt placement. Characterized by disproportionate dilatation of the fourth ventricle on serial neuro-imaging, it is rarely encountered in the early course of preterm infants and the differentiating clinical features are subtle and non-specific. Clinical alertness and sonographic correlation hold the key to early diagnosis. We report an early emergence of TFV in an extremely low gestational age newborn (ELGAN) following fulminant Pseudomonas aeruginosa meningitis, approach to management, and the neurological outcome. Fourth ventricle entrapment as a complication of perinatally acquired Pseudomonas aeruginosa meningitis in a surviving ELGAN is extremely rare.

Recruitment in retractor bulbi muscle during eyeblink conditioning: EMG analysis and common-drive model.

To analyze properly the role of the cerebellum in classical conditioning of the eyeblink and nictitating membrane (NM) response, the control of conditioned response dynamics must be better understood. Previous studies have suggested that the control signal is linearly related to the CR as a result of recruitment within the accessory abducens motoneuron pool, which acts to linearize retractor bulbi muscle and NM response mechanics. Here we investigate possible recruitment mechanisms. Data came from simultaneous recordings of NM position and multiunit electromyographic (EMG) activity from the retractor bulbi muscle of rabbits during eyeblink conditioning, in which tone and periocular shock act as conditional and unconditional stimuli, respectively. Action potentials (spikes) were extracted and classified by amplitude. Firing rates of spikes with different amplitudes were analyzed with respect to NM response temporal profiles and total EMG spike firing rate. Four main regularities were revealed and quantified: 1) spike amplitude increased with response amplitude; 2) smaller spikes always appeared before larger spikes; 3) subsequent firing rates covaried for spikes of different amplitude, with smaller spikes always firing at higher rates than larger ones; and 4) firing-rate profiles were approximately Gaussian for all amplitudes. These regularities suggest that recruitment does take place in the retractor bulbi muscle during conditioned NM responses and that all motoneurons receive the same command signal (common-drive hypothesis). To test this hypothesis, a model of the motoneuron pool was constructed in which motoneurons had a range of intrinsic thresholds distributed exponentially, with threshold linearly related to EMG spike amplitude. Each neuron received the same input signal as required by the common-drive assumption. This simple model reproduced the main features of the data, suggesting that conditioned NM responses are controlled by a common-drive mechanism that enables simple commands to determine response topography in a linear fashion.

DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.

About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.

Anaphylaxis following the ingestion of flour contaminated by house dust mites--a report of two cases from Singapore.

This study presents two patients who developed anaphylaxis after eating mite-contaminated food, and also contains a survey of dust-mites contamination in flour samples from Singapore households. The clinical records of each patient was studied. Patient A developed anaphylaxis twenty minutes following the ingestion of home-made fried fish coated with Japanese flour, while Patient B developed similar life-threatening symptoms one hour after the ingestion of home baked scones. Both patients were NSAID-intolerant and had a history of allergic rhinitis. Skin prick tests showed a strong positive result for dust-mites and for extracts prepared from the ingested flour. Flour samples were also examined microscopically which revealed large numbers of live Dermatophagoides farinae dust-mites. A survey of 57 flour samples showed that 4 samples (7%) were contaminated with dust mites. The findings in the present study confirm that mite-contamination of flour exists in Singaporean households, and it may trigger anaphylaxis in susceptible individuals.

Diffuse Speckle Contrast Analysis Assisted Intraoperative Blood Flow Monitoring in the Rat Model of Femoral Arterial Occlusion.

The rodent model has been largely used for understanding specific disease pathophysiology, with low cost and the large spectrum from genetic strains. Here, we present a diffuse speckle contrast analysis (DSCA) system to measure blood flow changes non-invasively in rat's thigh and paw during femoral arterial occlusion (FAO) surgery which is the procedure for inducing peripheral arterial disease. The blood flow index in rat's paw showed significant decrease according to arterial occlusion. Moreover, we analyzed cross-correlation between two measurement positions. The results showed the affinity with hemodynamic response. In conclusion, the DSCA system secured the intraoperative blood flow monitoring during FAO surgery in a rat model.

Local regulation of blood flow in the feline jejunum. A possible role for endoluminally released substance P.

Serotonin and substance P of gastrointestinal origin have been measured by radioimmunoassay in the bowel lumen under basal and stimulated conditions. To investigate the possibility that local blood flow may be influenced by these endoluminal hormones, 26 cats were studied with exogenous serotonin and substance P infused endoluminally into isolated proximal jejunal segments in vivo. Regional blood flow was measured by using the radioactive microsphere technique before, during, and after the endoluminal instillation of two doses of substance P (3.9 and 30 ng/min) or serotonin (0.9 and 21 micrograms/min). Neither dose of substance P changed systemic blood pressure. Substance P at the low dose caused an increase in blood flow to the experimental jejunal mucosa (from 53 +/- 10 ml/min per 100 g to 102 +/- 20 ml/min per 100 g, P less than 0.01). The higher dose of endoluminal substance P similarly increased blood flow to the experimental jejunal mucosal fraction, and also increased blood flow to the experimental jejunal muscularis fraction (from 17 +/- 3 ml/min per 100 g to 23 +/- 3 ml/min per 100 g, P less than 0.02). Serotonin increased blood flow to the experimental jejunal muscularis only at the high dose (17 +/- 4 ml/min per 100 g to 25 +/- 4 ml/min per 100 g tissue, P less than 0.01). These results provide evidence for a dose-related local effect of endoluminal substance P on gastrointestinal blood flow.

Potent and specific action of the mGlu1 antagonists YM-298198 and JNJ16259685 on synaptic transmission in rat cerebellar slices.

BACKGROUND AND PURPOSE: Specific and selective inhibitors for mGlu1 receptors are presently inadequate. A new generation of non-competitive mGlu1 antagonists with low nanomolar potencies is emerging. We evaluated two new compounds, YM-298198 and JNJ16259685, for effectiveness, potency and specificity for the first time in a brain slice preparation. EXPERIMENTAL APPROACH: Patch-clamp recording of Purkinje neurones in cerebellar slices were obtained. The slow mGlu1-mediated EPSP was used to establish a concentration-response curve. Fast excitatory synaptic inputs were tested for non-specific effects. KEY RESULTS: YM-298198 and JNJ16259685 inhibited the synaptic activation of mGlu1 in a concentration-dependent manner (IC(50) values of 24 nM and 19 nM, respectively). The antagonists were slow to inhibit and to reverse on washout, probably due to their lipophilic nature. There were no non-specific effects on fast AMPA receptor-mediated synaptic transmission in the cerebellum. CONCLUSIONS AND IMPLICATIONS: These compounds are more than a thousand-fold more potent than previously available compounds. Their selectivity and specificity will be very useful for studying the role of mGlu1 receptors both in vitro and in vivo.

Angiosome based time series analysis of deep tissue perfusion using diffuse speckle contrast analysis.

An angiosome is a three dimensional volume of biological tissue which a specific artery governs. Although proven useful for vascular surgery, the direct relationship between arterial flow and microcirculation in specific angiosome remains controversial. Here, we present new optical approach, a four-channel diffuse speckle contrast analysis (DSCA) which can simultaneously measure blood perfusion at different foot area. Based on the hypothesis that same angiosome will support similar low frequency oscillation, we investigated cross-correlation among different DSCA channels. Our preliminary results show that the LFO signal from the channel closest to posterior tibial artery is leading the signal from the other channels.