Evidence for Cross-Protection Against Subsequent Febrile Respiratory Illness Episodes From Prior Infections by Different Viruses Among Singapore Military Recruits 2009-2014.

BACKGROUND: Few studies have evaluated the relative cross-protection conferred by infection with different groups of viruses through studies of sequential infections in humans. We investigated the presence of short-lived relative cross-protection conferred by specific prior viral infections against subsequent febrile respiratory illness (FRI). METHODS: Men enlisted in basic military training between December 2009 and December 2014 were recruited, with the first FRI as the study entry point. ResPlex II assays and real-time polymerase chain reaction assays were used to detect viral pathogens in nasal wash samples, and survival analyses were performed to determine whether infection with particular viruses conferred short-lived relative cross-protection against FRI. RESULTS: Prior infection with adenovirus (hazard ratio [HR], 0.24; 95% confidence interval [CI], .14-.44) or influenza virus (HR, 0.52; 95% CI, .38-.73) conferred relative protection against subsequent FRI episode. Results were statistically significant even after adjustment for the interval between enlistment and FRI (P < .001). Adenovirus-positive participants with FRI episodes tended to be protected against subsequent infection with adenovirus, coronavirus, enterovirus/rhinovirus, and influenza virus (P = .062-.093), while men with influenza virus-positive FRI episodes tended be protected against subsequent infection with adenovirus (P = .044) and influenza virus (P = .081). CONCLUSION: Prior adenovirus or influenza virus infection conferred cross-protection against subsequent FRI episodes relative to prior infection due to other circulating viruses.

Epidemiology and Relative Severity of Influenza Subtypes in Singapore in the Post-Pandemic Period from 2009 to 2010.

BACKGROUND: After 2009, pandemic influenza A(H1N1) [A(H1N1)pdm09] cocirculated with A(H3N2) and B in Singapore. METHODS: A cohort of 760 participants contributed demographic data and up to 4 blood samples each from October 2009 to September 2010. We compared epidemiology of the 3 subtypes and investigated evidence for heterotypic immunity through multivariable logistic regression using a generalized estimating equation. To examine age-related differences in severity between subtypes, we used LOESS (locally weighted smoothing) plots of hospitalization to infection ratios and explored birth cohort effects referencing the pandemic years (1957; 1968). RESULTS: Having more household members aged 5-19 years and frequent public transport use increased risk of infection, while preexisting antibodies against the same subtype (odds ratio [OR], 0.61; P = .002) and previous influenza infection against heterotypic infections (OR, 0.32; P = .045) were protective. A(H1N1)pdm09 severity peaked in those born around 1957, while A(H3N2) severity was least in the youngest individuals and increased until it surpassed A(H1N1)pdm09 in those born in 1952 or earlier. Further analysis showed that severity of A(H1N1)pdm09 was less than that for A(H3N2) in those born in 1956 or earlier (P = .021) and vice versa for those born in 1968 or later (P < .001), with no difference in those born between 1957 and 1967 (P = .632). CONCLUSIONS: Our findings suggest that childhood exposures had long-term impact on immune responses consistent with the theory of antigenic sin. This, plus observations on short-term cross-protection, have implications for vaccination and influenza epidemic and pandemic mitigation strategies.

Results from a Patient-Based Health Education Intervention in Reducing Antibiotic Use for Acute Upper Respiratory Tract Infections in the Private Sector Primary Care Setting in Singapore.

We investigated the efficacy of patient-targeted education in reducing antibiotic prescriptions for upper respiratory tract infections (URTIs) among adults in the private primary care setting in Singapore. Our randomized controlled trial enrolled patients aged 21 years and above presenting at general practitioner (GP) clinics with URTI symptoms for 7 days or less. Intervention arm patients were verbally educated via pamphlets about the etiology of URTIs, the role of antibiotics in treating URTIs, and the consequences of inappropriate antibiotic use. Control arm patients were educated on influenza vaccinations. Both arms were compared regarding the proportions prescribed antibiotics and the patients' postconsultation views. A total of 914 patients consulting 35 doctors from 24 clinics completed the study (457 in each arm). The demographics of patients in both arms were similar, and 19.1% were prescribed an antibiotic, but this varied from 0% to 70% for individual GPs. The intervention did not significantly reduce antibiotic prescriptions (odds ratio [OR], 1.20; 95% confidence interval [CI], 0.83-1.73) except in patients of Indian ethnicity (OR, 0.28; 95% CI, 0.09-0.93). Positive associations between the intervention and the view that antibiotics were not needed most of the time for URTIs (P = 0.047) and on being worried about the side effects of antibiotics (P = 0.018) were restricted to the Indian subgroup. GPs in limited liability partnerships or clinic chains prescribed less (OR, 0.36; 95% CI, 0.14 to 0.92), while certain inappropriate patient responses were associated with the receipt of antibiotics. Follow-up studies to investigate differences in responses to educational programs between ethnicities and to explore GP-targeted interventions are recommended.

Knowledge, attitudes and practices towards antibiotic use in upper respiratory tract infections among patients seeking primary health care in Singapore.

BACKGROUND: Patients' expectations can influence antibiotic prescription by primary healthcare physicians. We assessed knowledge, attitude and practices towards antibiotic use for upper respiratory tract infections (URTIs), and whether knowledge is associated with increased expectations for antibiotics among patients visiting primary healthcare services in Singapore. METHODS: Data was collected through a cross-sectional interviewer-assisted survey of patients aged ≥21 years waiting to see primary healthcare practitioners for one or more symptoms suggestive of URTI (cough, sore throat, runny nose or blocked nose) for 7 days or less, covering the demographics, presenting symptoms, knowledge, attitudes, beliefs and practices of URTI and associated antibiotic use. Univariate and multivariate logistic regression was used to assess independent factors associated with patients' expectations for antibiotics. RESULTS: Nine hundred fourteen out of 987 eligible patients consulting 35 doctors were recruited from 24 private sector primary care clinics in Singapore. A third (307/907) expected antibiotics, of which a substantial proportion would ask the doctor for antibiotics (121/304, 40 %) and/or see another doctor (31/304, 10 %) if antibiotics were not prescribed. The majority agreed "antibiotics are effective against viruses" (715/914, 78 %) and that "antibiotics cure URTI faster" (594/912, 65 %). Inappropriate antibiotic practices include "keeping antibiotics stock at home" (125/913, 12 %), "taking leftover antibiotics" (114/913, 14 %) and giving antibiotics to family members (62/913, 7 %). On multivariate regression, the following factors were independently associated with wanting antibiotics (odds ratio; 95 % confidence interval): Malay ethnicity (1.67; 1.00-2.79), living in private housing (1.69; 1.13-2.51), presence of sore throat (1.50; 1.07-2.10) or fever (1.46; 1.01-2.12), perception that illness is serious (1.70; 1.27-2.27), belief that antibiotics cure URTI faster (5.35; 3.76-7.62) and not knowing URTI resolves on its own (2.18; 1.08-2.06), while post-secondary education (0.67; 0.48-0.94) was inversely associated. Those with lower educational levels were significantly more likely to have multiple misconceptions about antibiotics. CONCLUSION: Majority of patients seeking primary health care in Singapore are misinformed about the role of antibiotics in URTI. Agreeing with the statement that antibiotics cure URTI faster was most strongly associated with wanting antibiotics. Those with higher educational levels were less likely to want antibiotics, while those with lower educational levels more likely to have incorrect knowledge.

hnRNP K suppresses apoptosis independent of p53 status by maintaining high levels of endogenous caspase inhibitors.

Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related deaths globally. One of the cellular hallmarks of this disease is dysregulation of apoptosis, and a better understanding of this process is important if progress is to be made toward effectively treating HCC. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a RNA-binding protein that is implicated in apoptosis and is upregulated in various cancers, including HCC. In this study, we report new evidence for a crucial role of hnRNP K in suppressing apoptosis in HCC cells. We used the chemotherapeutic agent 5-fluorouracil to induce apoptosis in HCC cell lines and found that hnRNP K was downregulated, independent of both p53 and caspases. Prolonged downregulation of hnRNP K using small interfering RNA (siRNA) significantly decreased cell viability and increased apoptosis in HCC cell lines in a p53-independent manner. Moreover, enhanced tumor necrosis factor-related apoptosis-inducing ligand potency, independent of BH3-interacting domain death agonist (BID) cleavage, was also observed in hnRNP K siRNA-treated cells. Examination of the underlying mechanism revealed that hnRNP K suppresses the activity of various caspases through controlling transcription of the caspase inhibitor XIAP. Taken together, this study establishes that hnRNP K plays an antiapoptotic role in HCC cell lines, independent of p53 status, via the maintenance of high levels of endogenous caspase inhibitors, and also identifies hnRNP K as a possible therapeutic marker for cancer treatment.

Validation of a Natural Language Processing Algorithm for Detecting Infectious Disease Symptoms in Primary Care Electronic Medical Records in Singapore.

BACKGROUND: Free-text clinical records provide a source of information that complements traditional disease surveillance. To electronically harness these records, they need to be transformed into codified fields by natural language processing algorithms. OBJECTIVE: The aim of this study was to develop, train, and validate Clinical History Extractor for Syndromic Surveillance (CHESS), an natural language processing algorithm to extract clinical information from free-text primary care records. METHODS: CHESS is a keyword-based natural language processing algorithm to extract 48 signs and symptoms suggesting respiratory infections, gastrointestinal infections, constitutional, as well as other signs and symptoms potentially associated with infectious diseases. The algorithm also captured the assertion status (affirmed, negated, or suspected) and symptom duration. Electronic medical records from the National Healthcare Group Polyclinics, a major public sector primary care provider in Singapore, were randomly extracted and manually reviewed by 2 human reviewers, with a third reviewer as the adjudicator. The algorithm was evaluated based on 1680 notes against the human-coded result as the reference standard, with half of the data used for training and the other half for validation. RESULTS: The symptoms most commonly present within the 1680 clinical records at the episode level were those typically present in respiratory infections such as cough (744/7703, 9.66%), sore throat (591/7703, 7.67%), rhinorrhea (552/7703, 7.17%), and fever (928/7703, 12.04%). At the episode level, CHESS had an overall performance of 96.7% precision and 97.6% recall on the training dataset and 96.0% precision and 93.1% recall on the validation dataset. Symptoms suggesting respiratory and gastrointestinal infections were all detected with more than 90% precision and recall. CHESS correctly assigned the assertion status in 97.3%, 97.9%, and 89.8% of affirmed, negated, and suspected signs and symptoms, respectively (97.6% overall accuracy). Symptom episode duration was correctly identified in 81.2% of records with known duration status. CONCLUSIONS: We have developed an natural language processing algorithm dubbed CHESS that achieves good performance in extracting signs and symptoms from primary care free-text clinical records. In addition to the presence of symptoms, our algorithm can also accurately distinguish affirmed, negated, and suspected assertion statuses and extract symptom durations.