Noncoding RNome as Enabling Biomarkers for Precision Health.

Noncoding RNAs (ncRNAs), in the form of structural, catalytic or regulatory RNAs, have emerged to be critical effectors of many biological processes. With the advent of new technologies, we have begun to appreciate how intracellular and circulatory ncRNAs elegantly choreograph the regulation of gene expression and protein function(s) in the cell. Armed with this knowledge, the clinical utility of ncRNAs as biomarkers has been recently tested in a wide range of human diseases. In this review, we examine how critical factors govern the success of interrogating ncRNA biomarker expression in liquid biopsies and tissues to enhance our current clinical management of human diseases, particularly in the context of cancer. We also discuss strategies to overcome key challenges that preclude ncRNAs from becoming standard-of-care clinical biomarkers, including sample pre-analytics standardization, data cross-validation with closer attention to discordant findings, as well as correlation with clinical outcomes. Although harnessing multi-modal information from disease-associated noncoding RNome (ncRNome) in biofluids or in tissues using artificial intelligence or machine learning is at the nascent stage, it will undoubtedly fuel the community adoption of precision population health.

The effects of glucagon-like peptide (GLP)-1 receptor agonists on weight and glycaemic control in Prader-Willi syndrome: A systematic review.

OBJECTIVE: The mainstay management of hyperphagia and obesity in Prader-Willi syndrome (PWS) relies on dietary restrictions, strict supervision and behavioural modifications, which can be stressful for the patient and caregiver. There is no established pharmacological strategy to manage this aspect of PWS. Theoretically, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1-RA) used in patients with obesity and type 2 diabetes mellitus (T2DM) may be efficacious in weight and glycaemic control of PWS patients. We conducted a systematic review of the literature to summarize the evidence on the use of GLP1-RA in PWS patients. DESIGN: Primary studies were searched in major databases using key concepts 'Prader-Willi syndrome' and 'GLP1 receptor agonist' and outcomes, 'weight control OR glycaemic control OR appetite regulation'. RESULTS: Ten studies included, summarizing GLP1-RA use in 23 PWS patients (age, 13-37 years), who had used either exenatide (n = 14) or liraglutide (n = 9) over a duration of 14 weeks to 4 years. Sixteen (70%) of these patients had T2DM. Ten patients experienced improvement in body mass index, ranging from 1.5 to 16.0 kg/m2 , while improvement in HbA1c was seen in 19 of 23 cases, ranging between 0.3% and 7.5%. All five studies reporting appetite or satiety showed improvement in satiety levels. There were no reported serious side effects. CONCLUSIONS: GLP1-RA appears safe in PWS patients and may have potential benefits for weight, glycaemic and appetite control. Nonetheless, we also highlight a significant gap in the literature on the lack of well-designed studies in this area, which limits the recommendation of GLP1-RA use in PWS patients at present.

Impact of work routines on parents' and children's sleep during the COVID-19 pandemic lockdown.

OBJECTIVE: To evaluate the effects of parental sleep and work arrangements on children's sleep duration during the national lockdown period, referred to as 'Circuit Breaker' (CB), due to COVID-19. METHODS: Cross-sectional, anonymous, online questionnaire to parents with school-going children aged between 3 and 16 years. Child and parental sleep duration in relation to change in parental work arrangements, housing type and number of individuals in the household as reported by parents were evaluated. Descriptive statistics and tests of comparison were used to evaluate data. RESULTS: School-going children (n = 593) had a mean age of 8.68 (SD = 3.65; median 7) years. Both, fathers and mothers had gains in sleep during CB (based on self-reported sleep data), compared to pre-CB. Change in both maternal and paternal sleep duration positively correlated with change in child sleep duration (based on parent-reported sleep data) among all children (r2 = 0.27, p < 0.001 and r2 = 0.17, p < 0.001 respectively); pre-schoolers mirrored their mothers' sleep more closely. Parents who changed to working from home during the CB (compared to working from outside home previously) had the greatest gains in sleep during this period. Housing type was not significantly associated with change in child sleep duration from pre-CB to CB. CONCLUSIONS: Greater gains in sleep in parents was associated with working from home during CB. Child sleep duration mirrored gains in parental sleep, especially in pre-school and primary-school-going children. Optimising parental sleep may therefore be one of the means to improve child sleep.

School closure during the coronavirus disease 2019 (COVID-19) pandemic - Impact on children's sleep.

OBJECTIVE: To evaluate the sleep habits of school-going children before and during school closure in the national lockdown period (called 'Circuit Breaker' or CB in Singapore) due to the COVID-19 pandemic. METHODS: Cross-sectional, anonymous, online, population-based survey questionnaire was administered to parents aged 21 years and above with children aged between 3 and 16 years attending pre-school, primary or secondary school (equivalent to kindergarten, middle and-high school) and residing in Singapore. Sleep duration in relation to various daily activities including academic activities, physical exercise, and screen time was evaluated pre-CB and during CB. RESULTS: Data from 593 participants were analyzed. Pre-CB, the overall mean (SD) sleep duration of the study population was 9.01 (1.18) hours on weekdays and 9.99 (0.94) hours on weekends. During CB, mean (SD) sleep duration overall was 9.63 (1.18) hours. Although children generally went to bed later (mean 0.65 h later), they woke up even later during CB (mean 1.27 h later), resulting in longer sleep duration (mean increase of 0.35 h). This was most evident in secondary school children (mean increase of 0.70 h). Children attending private schools (which had later start times) had increased sleep duration (mean 10.01 (SD 0.89) hours pre-CB and 10.05 (SD 0.93) hours during CB) compared to public schools (mean 9.05 (SD 0.91) pre-CB and 9.49 (SD 1.22) hours during CB). CONCLUSIONS: School closure from the COVID-19 pandemic resulted in longer sleep duration in school-going children. Early school/academic activity start times had a significant impact on limiting children's sleep duration.

A randomised clinical trial to evaluate the safety, fit, comfort of a novel N95 mask in children.

Children are more vulnerable to the risks of air pollution, including susceptibility to acquiring chronic diseases in their developing lungs. Despite these, there are no specific masks designed for and tested in children that are available to protect our young from the common particulate air pollutants today. We evaluated safety, fit and comfort of a specially designed paediatric N95 mask with an optional micro ventilator (micro fan, MF) in healthy children aged 7-14 years, in a randomized, two-period crossover design. The subjects' cardiorespiratory physiological measurements were assessed in different states of physical activity under different interventions (mask without and with MF). A total of 106 subjects were recruited between July-August 2016. The use of the mask without MF increased the End-Tidal CO2 (ETCO2) and Fractional concentration of Inspired CO2 (FICO2) at rest and on mild exertion, as expected. The use of the mask with MF brought FICO2 levels comparably closer to baseline levels without the mask for both activities. The mask, with or without the MF, was found to be well fitting, comfortable and safe for use in children at rest and on mild exertion. The N95 mask tested offers a promising start for more studies in the paediatric population.

A novel model for predicting non-responsiveness to intravenous immunoglobulins in Kawasaki disease: The Singapore experience.

AIM: We aimed to assess the utility of four published risk-scoring methods in predicting intravenous immunoglobulins (IVIG) non-responsiveness in Kawasaki disease (KD) patients from Singapore and develop a new predictive model. METHODS: We reviewed the medical records of 215 KD children. The performance of existing scoring methods in identifying non-responsive cases based on sensitivities (SN) and specificities (SP) was evaluated in 122 Singaporean Chinese. From our dataset, a model involving six predictors was built. RESULTS: The following respective SN (%) and SP (%) were obtained: Egami: 26%, 68%; Kobayashi: 21%, 62%; Sano: 13%, 86% and Fukunishi: 46%, 71%. These results indicated that the existing scoring methods performed poorly compared to those reported in their respective original publications, which ranged between 68 and 87%. The new predictive model was derived with an improved SN (80%) and SP (80%). CONCLUSIONS: Currently available risk-scoring methods have less applicability in the Singaporean Chinese population. The proposed new risk-scoring predictive model derived based on data from Chinese cohort demonstrated much better SN and SP.

A meta-analysis of transcatheter device closure of perimembranous ventricular septal defect.

BACKGROUND: While transcatheter device closure of ventricular septal defects (VSDs) is gaining popularity, concerns remain about adverse events; particularly heart block in peri-membranous VSDs (pmVSDs). The aim of this study is to ascertain outcomes of transcatheter device closure of pmVSDs through a meta-analysis of current literature. METHODS: A PubMed and Scopus search for studies in English on device closure of pmVSDs published till end-February 2017 was performed. Exclusion criteria included case series already included in multi-centre studies, sample size <5, and VSD acquired following myocardial infarction. Pooled estimates of success and complications was obtained using the random effects model. RESULTS: A total of 54 publications comprising 6762 patients with pmVSDs were included. The mean age of patients ranged from 1.6 to 37.4years. The pooled estimate of successful device implantation is 97.8% (95% CI: 96.8 to 98.6). The most common complication is residual shunt (15.9%; 95% CI: 10.9 to 21.5). Other complications include arrhythmias (10.3%; 95% CI: 8.3 to 12.4) and valvular defects (4.1%; 95% CI: 2.4 to 6.1). The pooled estimate of complete atrioventricular block (cAVB) is 1.1% (95% CI: 0.5 to 1.9). CONCLUSION: Our meta-analysis suggests that device closure of pmVSDs is a safe and effective procedure. The complication of cAVB is low but significant. The risk is expected to further reduce with newer devices which are less stiff with improved profiles. Further studies validating this will be useful in formulating guidelines for device closure of pmVSDs.

A systematic review and meta-analysis of outcomes of transcatheter stent implantation for the primary treatment of native coarctation.

BACKGROUND/OBJECTIVES: The treatment of native coarctation of aorta (CoA) has evolved since surgery performed in 1944, followed by transcatheter balloon angioplasty and recently, widely adopted stent implantation. Despite good results demonstrated with stent implantation, a systematic review and meta-analysis (SRMA) looking at the efficacy and safety of the intervention, particularly in younger population is yet to be done. We aimed to obtain pooled estimates of the success and complication rates after transcatheter stent implantation in the treatment of native CoA based on SRMA. METHODS: We searched literature published until 31 Dec. 2015, reporting outcomes of transcatheter stent implantation in the treatment of native CoA. The pooled estimates were obtained using the random effect model. RESULTS: Seventeen reports comprising 561 patients were included. Fourteen studies reported 100% success rate, the lowest was 77%, the largest study reported 81% using a definition of systolic pressure difference of less than 15mmHg. The pooled estimate of overall success rate was 98% (95% CI: 94.5-100.0; I2=65%, heterogeneity test p<0.001). Six out of 17 studies reported zero complication. Two studies, however, reported complications in almost half of the cohort. The pooled estimate of rate of complications was 10% (95% CI: 5.1-15.5; I2=72%, heterogeneity test p<0.001). Three studies comprising only children, 62, with mean age of 11.1 (4-19) years reported high mean success rate at 98% with only 1 failure. CONCLUSIONS: There is a high success rate with a small complication rate with stent implantations for native CoA even as the treatment is brought to younger age group.

Topical Review: Mind Your Language-Translation Matters (A Narrative Review of Translation Challenges).

OBJECTIVE: Translation of developmental-behavioral screening tools for use worldwide can be daunting. We summarize issues in translating these tools. METHODS: Instead of a theoretical framework of "equivalence" by Pena and International Test Commission guidelines, we decided upon a practical approach used by the American Association of Orthopedic Surgeons (AAOS). We derived vignettes from the Parents' Evaluation of Developmental Status manual and published literature and mapped them to AAOS. RESULTS: We found that a systematic approach to planning and translating developmental-behavioral screeners is essential to ensure "equivalence" and encourage wide consultation with experts. CONCLUSION: Our narrative highlights how translations can result in many challenges and needed revisions to achieve "equivalence" such that the items remain consistent, valid, and meaningful in the new language for use in different cultures. Information sharing across the community of researchers is encouraged. This narrative may be helpful to novice researchers.

Longitudinal evaluation of P-wave dispersion and P-wave maximum in children after transcatheter device closure of secundum atrial septal defect.

Transcatheter device closure of the secundum atrial septal defect (ASD) in children prevents atrial arrhythmias in older age. However, the benefits of favourable atrial electrocardiographic markers in these children remain elusive. We aimed to review the electrocardiographic markers of atrial activity in a longitudinal fashion. We retrospectively reviewed longitudinal data of all children who underwent transcatheter device closure at the National University Hospital between 2004 and 2013. The inclusion criteria included the presence of a secundum-type ASD with left to right shunt and evidence of increased right ventricular volume load (Q p/Q s ratio >1.5 and/or right ventricular dilatation). A total of 25 patients with a mean follow-up of 44.7 ± 33.47 (7.3-117.4) months were included. P maximum and P dispersion decreased at 2 months, P amplitude at 1 week and remained so until last follow-up. A positive trend was seen with a correlation coefficient of +0.12 for P maximum, +0.08 for P dispersion and 0.34 for P amplitude. There was a higher baseline P amplitude and P dispersion in patients who were older than 10 years and a non-significant trend to support an increase in both P maximum (71.0 ± 8.8 vs. 73.2 ± 12.7), P dispersion (17.0 ± 6.5 vs. 22.0 ± 11.3) and P amplitude (0.88 ± 0.25 vs. 1.02 ± 0.23) in patients with an ASD more than 15 mm compared with an ASD <15 mm. There is reduction in both P maximum and P dispersion as early as 2 months, which persisted on follow-up. Earlier closure may result in more favourable electrocardiographic results.

Hyperbaric oxygen therapy in necrotising soft tissue infections: a study of patients in the United States Nationwide Inpatient Sample.

PURPOSE: Necrotising soft tissue infection (NSTI) is a deadly disease associated with a significant risk of mortality and long-term disability from limb and tissue loss. The aim of this study was to determine the effect of hyperbaric oxygen (HBO(2)) therapy on mortality, complication rate, discharge status/location, hospital length of stay and inflation-adjusted hospitalisation cost in patients with NSTI. METHODS: This was a retrospective study of 45,913 patients in the Nationwide Inpatient Sample (NIS) from 1988 to 2009. RESULTS: A total of 405 patients received HBO(2) therapy. The patients with NSTI who received HBO(2) therapy had a lower mortality (4.5 vs. 9.4 %, p = 0.001). After adjusting for predictors and confounders, patients who received HBO(2) therapy had a statistically significantly lower risk of dying (odds ratio (OR) 0.49, 95 % confidence interval (CI) 0.29-0.83), higher hospitalisation cost (US$52,205 vs. US$45,464, p = 0.02) and longer length of stay (LOS) (14.3 days vs. 10.7 days, p < 0.001). CONCLUSIONS: This retrospective analysis of HBO(2) therapy in NSTI showed that despite the higher hospitalisation cost and longer length of stay, the statistically significant reduction in mortality supports the use of HBO(2) therapy in NSTI.

Laparoscopic appendectomy outcomes on the weekend and during the week are no different: a national study of 151,774 patients.

BACKGROUND: The "weekend effect" is defined as increased morbidity and mortality for patients admitted on weekends compared with weekdays. It has been observed for several diseases, including myocardial infarction and renal insufficiency; however, it has not yet been investigated for laparoscopic appendectomy in acute appendicitis-one of the most prevalent surgical diagnoses. METHODS: The present study is based on the Nationwide Inpatient Sample (NIS) from 1999 to 2008. The following outcomes were compared between patients undergoing laparoscopic appendectomy for acute appendicitis admitted on weekdays versus weekends: severity of appendicitis, intraoperative and postoperative complications, conversion rate, in-hospital mortality, and length of hospital stay. Unadjusted and risk-adjusted generalized linear regression analyses were performed. RESULTS: Overall, 151,774 patients were included, mean age was 39.6 years, 52.6% (n = 79,801) were male, and 25.3% (n = 38,317) were admitted on weekends. After risk adjustment, the conversion rate was lower [odds ratio (OR): 0.94, p = 0.004, number needed to harm (NNH): 244], whereas pulmonary complications (OR: 1.12, p = 0.028, NNH: 649) and reoperations (OR: 1.21, p = 0.013, NNH: 1,028) were slightly higher on weekends than on weekdays. Overall postoperative complications (OR: 1.03, p = 0.24), mortality (OR: 1.37, p = 0.075) and length of hospital stay (mean on weekday: 2.00 days, weekends: 2.01 days, p = 0.29) were not statistically different. CONCLUSIONS: The present investigation provides evidence that no clinically significant "weekend effect" for patients undergoing laparoscopic appendectomy exists. Therefore, hospital or staffing policy changes are not justified based on the findings from this large national study.

Cholecystectomy concomitant with laparoscopic gastric bypass: a trend analysis of the nationwide inpatient sample from 2001 to 2008.

BACKGROUND: Gallstone formation is common in obese patients, particularly during rapid weight loss. Whether a concomitant cholecystectomy should be performed during laparoscopic gastric bypass surgery is still contentious. We aimed to analyze trends in concomitant cholecystectomy and laparoscopic gastric bypass surgery (2001-2008), to identify factors associated with concomitant cholecystectomy, and to compare short-term outcomes after laparoscopic gastric bypass with and without concomitant cholecystectomy. METHODS: We used data from adults undergoing laparoscopic gastric bypass for obesity from the Nationwide Inpatient Sample. The Cochran-Armitage trend test was used to assess changes over time. Unadjusted and risk-adjusted generalized linear models were performed to assess predictors of concomitant cholecystectomy and to assess postoperative short-term outcomes. RESULTS: A total of 70,287 patients were included: mean age was 43.1 years and 81.6% were female. Concomitant cholecystectomy was performed in 6,402 (9.1%) patients. The proportion of patients undergoing concomitant cholecystectomy decreased significantly from 26.3% in 2001 to 3.7% in 2008 (p for trend < 0.001). Patients who underwent concomitant cholecystectomy had higher rates of mortality (unadjusted odds ratios [OR], 2.16; p = 0.012), overall postoperative complications (risk-adjusted OR, 1.59; p = 0.001), and reinterventions (risk-adjusted OR, 3.83; p < 0.001), less frequent routine discharge (risk-adjusted OR, 0.70; p = 0.05), and longer adjusted hospital stay (median difference, 0.4 days; p < 0.001). CONCLUSIONS: Concomitant cholecystectomy and laparoscopic gastric bypass surgery have decreased significantly over the last decade. Given the higher rates of postoperative complications, reinterventions, mortality, as well as longer hospital stay, concomitant cholecystectomy should only be considered in patients with symptomatic gallbladder disease.

Global research coaching in orthopedic surgery: seeding for an international network.

Despite the importance of delivering evidence-based health care, orthopedic surgeons have directed fewer efforts towards the generation of such evidence. Even when present, published evidence lacks methodological rigor and is known to be inaccurate. One of the main reasons for the lack of generation of quality evidence, and the low involvement in research among orthopedic surgeons, is the lack of structured research coaching environments where they can learn concepts and hone their research skills. There is a palpable need for a pragmatic and outcome-oriented approach that can equip orthopedic surgeons with effective ways of communicating their research in writing. We describe a pragmatic research coaching program, designed and developed by the Research on Research group, which aims to build a global network of orthopedic researchers trained in streamlined and standardized research methods. We also provide a brief overview of the course principles and tools, and the platforms used in this program.

Treinamento em pesquisa global em cirurgia ortopédica: semente para uma rede internacional / Global research coaching in orthopedic surgery: seeding for an international network

Apesar da importância de praticar o atendimento de saúde baseado em evidências, os cirurgiões ortopedistas têm direcionado poucos esforços para gerar essas evidências. Mesmo quando presente, a evidência publicada é falha quanto ao rigor metodológico e sabe-se que é imprecisa. Um dos principais motivos para a falta de geração de evidências de qualidade é o baixo envolvimento dos cirurgiões ortopedistas na pesquisa e a falta de ambientes de treinamento estruturados em pesquisa, onde eles possam aprender conceitos, assim como aprimorar suas habilidades em pesquisa. Existe a necessidade de uma abordagem objetiva que possa equipar os cirurgiões ortopedistas com métodos eficientes para transitarem da pesquisa para a escrita. Descrevemos um programa pragmático de treinamento em pesquisa, planejado e desenvolvido pelo grupo de Pesquisa sobre Pesquisa, que visa montar uma rede global de pesquisadores ortopedistas treinados em métodos de pesquisa funcionais e padronizados. Também fornecemos um rápido panorama sobre os princípios do curso e suas ferramentas, assim como plataformas usadas nesse programa.

Despite the importance of delivering evidence-based health care, orthopedic surgeons have directed fewer efforts towards the generation of such evidence. Even when present, published evidence lacks methodological rigor and is known to be inaccurate. One of the main reasons for the lack of generation of quality evidence, and the low involvement in research among orthopedic surgeons, is the lack of structured research coaching environments where they can learn concepts and hone their research skills. There is a palpable need for a pragmatic and outcome-oriented approach that can equip orthopedic surgeons with effective ways of communicating their research in writing. We describe a pragmatic research coaching program, designed and developed by the Research on Research group, which aims to build a global network of orthopedic researchers trained in streamlined and standardized research methods. We also provide a brief overview of the course principles and tools, and the platforms used in this program.

Patterns of herbal combination for the treatment of insomnia commonly employed by highly experienced Chinese medicine physicians.

OBJECTIVE: To explore the most effective herbal combinations commonly used by highly experienced Chinese medicine (CM) physicians for the treatment of insomnia. METHODS: We collected and analyzed data related to insomnia treatment from the clinics of 7 highly experienced CM physicians in Beijing. The sample included 162 patients and 460 consultations in total. Patient outcomes, such as sleep quality and sleep time per day, were manually collected from the medical records by trained CM clinicians. Three data mining methods, support vector machine (SVM), logistic regression and decision tree, and multifactor dimensionality reduction (MDR), were used to determine and confirm the herbal combinations that resulted in positive outcomes in patients suffering from insomnia. RESULTS: Results show that MDR is the most efficient method to predict the effective herbal combinations. Using the MDR model, we identified several combinations of herbs with 100% positive outcomes, such as stir-fried spine date seed, Szechwan lovage rhizome, and prepared thinleaf milkwort root; white peony root, golden thread, and stir-fried spine date seed; and Asiatic cornelian cherry fruit with fresh rehmannia. CONCLUSIONS: Results indicate that herbal combinations are effective treatments for patients with insomnia compared with individual herbs. It is also shown that MDR is a potent data mining method to identify the herbal combination with high rates of positive outcome.