Predictive Value of Proteinuria in Adult Dengue Severity

Background

Dengue is an important viral infection with different presentations. Predicting disease severity is important in triaging patients requiring hospital care. We aim to study the value of proteinuria in predicting the development of dengue hemorrhagic fever (DHF), utility of urine dipstick test as a rapid prognostic tool.

Methodology and principal findings

Adult patients with undifferentiated fever (n = 293) were prospectively enrolled at the Infectious Disease Research Clinic at Tan Tock Seng Hospital, Singapore from January to August 2012. Dengue infection was confirmed in 168 (57%) by dengue RT-PCR or NS1 antigen detection. Dengue cases had median fever duration of 6 days at enrolment. DHF was diagnosed in 34 cases according to the WHO 1997 guideline. Dengue fever (DF) patients were predominantly younger and were mostly seen in the outpatient setting with higher platelet level. Compared to DF, DHF cases had significantly higher peak urine protein creatinine ratio (UPCR) during clinical course (26 vs. 40 mg/mmol; p<0.001). We obtained a UPCR cut-off value of 29 mg/mmol based on maximum AUC in ROC curves of peak UPCR for DF versus DHF, corresponding to 76% sensitivity and 60% specificity. Multivariate analysis with other readily available clinical and laboratory variables increased the AUC to 0.91 with 92% sensitivity and 80% specificity. Neither urine dipstick at initial presentation nor peak urine dipstick value during the entire illness was able to discriminate between DF and DHF.

Conclusions

Proteinuria measured by a laboratory-based UPCR test may be sensitive and specific in prognosticating adult dengue patients.     

Serum Metabolome and Lipidome Changes in Adult Patients with Primary Dengue Infection

Background

Dengue virus (DENV) is the most widespread arbovirus with an estimated 100 million infections occurring every year. Endemic in the tropical and subtropical areas of the world, dengue fever/dengue hemorrhagic fever (DF/DHF) is emerging as a major public health concern. The complex array of concurrent host physiologic changes has hampered a complete understanding of underlying molecular mechanisms of dengue pathogenesis.

Methodology/Principle Findings

Systems level characterization of serum metabolome and lipidome of adult DF patients at early febrile, defervescence, and convalescent stages of DENV infection was performed using liquid chromatography- and gas chromatography-mass spectrometry. The tractability of following metabolite and lipid changes in a relatively large sample size (n = 44) across three prominent infection stages allowed the identification of critical physiologic changes that coincided with the different stages. Sixty differential metabolites were identified in our metabolomics analysis and the main metabolite classes were free fatty acids, acylcarnitines, phospholipids, and amino acids. Major perturbed metabolic pathways included fatty acid biosynthesis and β-oxidation, phospholipid catabolism, steroid hormone pathway, etc., suggesting the multifactorial nature of human host responses. Analysis of phospholipids and sphingolipids verified the temporal trends and revealed association with lymphocytes and platelets numbers. These metabolites were significantly perturbed during the early stages, and normalized to control levels at convalescent stage, suggesting their potential utility as prognostic markers.

Conclusions/Significance

DENV infection causes temporally distinct serum metabolome and lipidome changes, and many of the differential metabolites are involved in acute inflammatory responses. Our global analyses revealed early anti-inflammatory responses working in concert to modulate early pro-inflammatory processes, thus preventing the host from development of pathologies by excessive or prolonged inflammation. This study is the first example of how an omic- approach can divulge the extensive, concurrent, and dynamic host responses elicited by DENV and offers plausible physiological insights to why DF is self limiting.     

Estimating Dengue Transmission Intensity from Sero-Prevalence Surveys in Multiple Countries

Background

Estimates of dengue transmission intensity remain ambiguous. Since the majority of infections are asymptomatic, surveillance systems substantially underestimate true rates of infection. With advances in the development of novel control measures, obtaining robust estimates of average dengue transmission intensity is key for assessing both the burden of disease from dengue and the likely impact of interventions.

Methodology/Principal Findings

The force of infection (λ) and corresponding basic reproduction numbers (R₀) for dengue were estimated from non-serotype (IgG) and serotype-specific (PRNT) age-stratified seroprevalence surveys identified from the literature. The majority of R₀ estimates ranged from 1–4. Assuming that two heterologous infections result in complete immunity produced up to two-fold higher estimates of R₀ than when tertiary and quaternary infections were included. λ estimated from IgG data were comparable to the sum of serotype-specific forces of infection derived from PRNT data, particularly when inter-serotype interactions were allowed for.

Conclusions/Significance

Our analysis highlights the highly heterogeneous nature of dengue transmission. How underlying assumptions about serotype interactions and immunity affect the relationship between the force of infection and R₀ will have implications for control planning. While PRNT data provides the maximum information, our study shows that even the much cheaper ELISA-based assays would provide comparable baseline estimates of overall transmission intensity which will be an important consideration in resource-constrained settings.     

Potential Harm of Prophylactic Platelet Transfusion in Adult Dengue Patients

BackgroundThrombocytopenia is a hallmark of dengue infection, and bleeding is a dreaded complication of dengue fever. Prophylactic platelet transfusion has been used to prevent bleeding in the management of dengue fever, although the evidence for its benefit is lacking. In adult dengue patients with platelet count <20,000/mm³ without bleeding, we aimed to assess if prophylactic platelet transfusion was effective in reducing clinical bleeding and other outcomes.MethodWe conducted a retrospective non-randomised observational study of dengue patients with platelet count < 20,000/mm³ without bleeding (except petechiae) admitted to Tan Tock Seng Hospital from January 2005 to December 2008. Baseline characteristics and clinical outcomes were compared between the non-transfused vs. transfused groups. Outcomes studied were clinical bleeding, platelet increment, hospital length of stay, intensive care unit admission and death.ResultsOf the 788 patients included, 486 received prophylactic platelet transfusion. There was no significant difference in the presence of clinical bleeding in the two groups (18.2% in non-transfused group vs. 23.5% in transfused group; P = 0.08). Patients in the transfused group took a median of 1 day longer than the non-transfused group to increase their platelet count to 50,000/mm³ or more (3 days vs. 2 days, P <0.0001). The median duration of hospital stay in the non-transfused group was 5 days vs. 6 days in the transfused group (P< 0.0001). There was no significant difference in the proportion requiring ICU admission (non-transfused 0.66% vs. transfused 1.23%, P = 0.44) and death (non-transfused 0% vs. transfused 0.2%, P = 0.43).ConclusionPlatelet transfusion in absence of bleeding in adult dengue with platelet count <20,000/mm³ did not reduce bleeding or expedite platelet recovery. There was potential harm by slowing recovery of platelet count to >50,000/mm³ and increasing length of hospitalization.     

Prevalence of Radiographic Osteoarthritis of the Knee and Its Relationship to Self-Reported Pain

Background and Aim

Osteoarthritis (OA) of the knee is one of the most common skeletal disorders, yet little data are available in Asian populations. We sought to assess the prevalence and pattern of radiographic OA of the knee, and its relationship to self-reported pain in a Vietnamese population.

Methods

The study was based on a sample of 170 men and 488 women aged ≥40 years who were randomly sampled from the Ho Chi Minh City (Vietnam). Radiographs of the knee were graded from 0 to 4 according to the Kellgren and Lawrence scale. Osteoarthritis was defined as being present in a knee if radiographic grades of 2 or higher were detected. Knee pain and symptoms were ascertained by direct interview using a structured questionnaire.

Results

The point prevalence of radiographic OA of the knee was 34.2%, with women having higher rate than men (35.3% vs 31.2%). The prevalence of knee OA increased with advancing age: 8% among those aged 40–49 years, 30% in those aged 50–59 years, and 61.1% in those aged ≥60 years. Greater BMI was associated with higher risk of knee OA. Self-reported knee pain was found in 35% of men and 62% of women. There was a statistically significant association between self-reported knee pain and knee OA (prevalence ratio 3.1; 95% CI 2.0 to 4.6).

Conclusions

These data indicate that approximately a third of Vietnamese men and women have radiographic OA in the knee, and that self-reported knee pain may be used as an indicator of knee osteoarthritis.     

Prevalence of Self-Reported Stroke and Disability in the French Adult Population: A Transversal Study

In France, the prevalence of stroke and the level of disability of stroke survivors are little known. The aim of this study was to evaluate functional limitations in adults at home and in institutions, with and without self-reported stroke. A survey named “the Disability Health survey” was carried out in people''s homes (DHH) and in institutions (DHI). Medical history and functional level (activities-of-daily-living, ADL and instrumented-activities-of-daily-living IADL) were collected through interviews. The modified Rankin score (mRS) and the level of dependence and disability were compared between participants with and without stroke. 33896 subjects responded. The overall prevalence of stroke was 1.6% (CI95% [1.4%–1.7%]). The mRS was over 2 for 34.4% of participants with stroke (28.7% of participants at home and 87.8% of participants in institutions) versus respectively 3.9%, 3.1% and 71.6% without stroke. Difficulty washing was the most frequently reported ADL for those with stroke (30.6% versus 3% for those without stroke). Difficulty with ADL and IADL increased with age but the relative risk was higher below the age of 60 (17 to 25) than over 85 years (1.5 to 2.2), depending on the ADL. In the overall population, 22.6% of those confined to bed or chair reported a history of stroke. These results thus demonstrate a high national prevalence of stroke. Older people are highly dependent, irrespective of stroke history and the relative risk of dependence in young subjects with a history of stroke is high compared with those without.     

Pain Intensity Recognition Rates via Biopotential Feature Patterns with Support Vector Machines

Background

The clinically used methods of pain diagnosis do not allow for objective and robust measurement, and physicians must rely on the patient’s report on the pain sensation. Verbal scales, visual analog scales (VAS) or numeric rating scales (NRS) count among the most common tools, which are restricted to patients with normal mental abilities. There also exist instruments for pain assessment in people with verbal and / or cognitive impairments and instruments for pain assessment in people who are sedated and automated ventilated. However, all these diagnostic methods either have limited reliability and validity or are very time-consuming. In contrast, biopotentials can be automatically analyzed with machine learning algorithms to provide a surrogate measure of pain intensity.

Methods

In this context, we created a database of biopotentials to advance an automated pain recognition system, determine its theoretical testing quality, and optimize its performance. Eighty-five participants were subjected to painful heat stimuli (baseline, pain threshold, two intermediate thresholds, and pain tolerance threshold) under controlled conditions and the signals of electromyography, skin conductance level, and electrocardiography were collected. A total of 159 features were extracted from the mathematical groupings of amplitude, frequency, stationarity, entropy, linearity, variability, and similarity.

Results

We achieved classification rates of 90.94% for baseline vs. pain tolerance threshold and 79.29% for baseline vs. pain threshold. The most selected pain features stemmed from the amplitude and similarity group and were derived from facial electromyography.

Conclusion

The machine learning measurement of pain in patients could provide valuable information for a clinical team and thus support the treatment assessment.     

Handling Ibuprofen Increases Pain Tolerance and Decreases Perceived Pain Intensity in a Cold Pressor Test

Pain contributes to health care costs, missed work and school, and lower quality of life. Extant research on psychological interventions for pain has focused primarily on developing skills that individuals can apply to manage their pain. Rather than examining internal factors that influence pain tolerance (e.g., pain management skills), the current work examines factors external to an individual that can increase pain tolerance. Specifically, the current study examined the nonconscious influence of exposure to meaningful objects on the perception of pain. Participants (N = 54) completed a cold pressor test, examined either ibuprofen or a control object, then completed another cold pressor test. In the second test, participants who previously examined ibuprofen reported experiencing less intense pain and tolerated immersion longer (relative to baseline) than those who examined the control object. Theoretical and applied implications of these findings are discussed.     

Psychometric Validation Study of the Liebowitz Social Anxiety Scale - Self-Reported Version for Brazilian Portuguese

Social Anxiety Disorder (SAD) is prevalent and rarely diagnosed due to the difficulty in recognizing its symptoms as belonging to a disorder. Therefore, the evaluation/screening scales are of great importance for its detection, with the most used being the Liebowitz Social Anxiety Scale (LSAS). Thus, this study proposed to evaluate the psychometric properties of internal consistency and convergent validity, as well as the confirmatory factorial analysis and reliability of the self-reported version of the LSAS (LSAS-SR), translated into Brazilian Portuguese, in a sample of the general population (N = 413) and in a SAD clinical sample (N = 252). The convergent validity with specific scales for the evaluation of SAD and a general anxiety scale presented correlations ranging from 0.21 to 0.84. The confirmatory factorial analysis did not replicate the previously indicated findings of the literature, with the difficulty being in obtaining a consensus factorial structure common to the diverse cultures in which the instrument was studied. The LSAS-SR presented excellent internal consistency (α = 0.90–0.96) and test-retest reliability (Intraclass Correlation Coefficient = 0.81; Pearson’s = 0.82). The present findings support those of international studies that attest to the excellent psychometric properties of the LSAS-SR, endorsing its status as the gold standard.     

Controlling Dengue with Vaccines in Thailand

Background

Dengue is a mosquito-borne infectious disease that constitutes a growing global threat with the habitat expansion of its vectors Aedes aegyti and A. albopictus and increasing urbanization. With no effective treatment and limited success of vector control, dengue vaccines constitute the best control measure for the foreseeable future. With four interacting dengue serotypes, the development of an effective vaccine has been a challenge. Several dengue vaccine candidates are currently being tested in clinical trials. Before the widespread introduction of a new dengue vaccine, one needs to consider how best to use limited supplies of vaccine given the complex dengue transmission dynamics and the immunological interaction among the four dengue serotypes.

Methodology/Principal Findings

We developed an individual-level (including both humans and mosquitoes), stochastic simulation model for dengue transmission and control in a semi-rural area in Thailand. We calibrated the model to dengue serotype-specific infection, illness and hospitalization data from Thailand. Our simulations show that a realistic roll-out plan, starting with young children then covering progressively older individuals in following seasons, could reduce local transmission of dengue to low levels. Simulations indicate that this strategy could avert about 7,700 uncomplicated dengue fever cases and 220 dengue hospitalizations per 100,000 people at risk over a ten-year period.

Conclusions/Significance

Vaccination will have an important role in controlling dengue. According to our modeling results, children should be prioritized to receive vaccine, but adults will also need to be vaccinated if one wants to reduce community-wide dengue transmission to low levels.     

Risk Factors for Fatality among Confirmed Adult Dengue Inpatients in Singapore: A Matched Case-Control Study

Objectives

To identify demographic, clinical and laboratory risk factors for death due to dengue fever in adult patients in Singapore.

Methods

Multi-center retrospective study of hospitalized adult patients with confirmed dengue fever in Singapore between 1 January 2004 and 31 December 2008. Non-fatal controls were selected by matching age and year of infection with fatal cases. World Health Organization 1997, 2009 criteria were applied to define dengue hemorrhagic fever (DHF), warning signs and severe dengue. Statistical significance was assessed by conditional logistic regression modeling.

Results

Significantly more fatal cases than matched controls had pre-existing co-morbid conditions, and presented with abdominal pain/tenderness. Median pulse rates were significantly higher while myalgia was significantly less frequent in cases. . Fatal cases also had higher leucocyte counts, platelet counts, serum sodium, potassium, urea, creatine and bilirubin levels on admission compared to controls. There was no statistical significant difference between the prevalence of DHF and hematocrit level among cases and controls. Multivariate analysis showed myalgia and leucocyte count at presentation were independent predictors of fatality (adjusted odds ratios 0.09 and 2.94 respectively). None of the controls was admitted to intensive care unit (ICU) or given blood transfusion, while 71.4% and 28.6% of fatal cases received ICU admission and blood transfusion.

Conclusions

Absence of myalgia and leucocytosis on admission were independently associated with fatality in our matched case-control study. Fatalities were also commonly associated with co-morbidities and clinicians should be alarmed if dengue patients fulfilled severe dengue case definition on admission.     

Increased Health Risk in Subjects with High Self-Reported Seasonality

Background

Seasonal variations in mood and behaviour, termed seasonality, are commonly reported in the general population. As a part of a large cross-sectional health survey in Hordaland, Norway, we investigated the relationship between seasonality, objective health measurements and health behaviours.

Methodology/Principal Findings

A total of 11,545 subjects between 40–44 years old participated, completing the Global Seasonality Score, measuring seasonality. Waist/hip circumference, BMI and blood pressure were measured, and blood samples were analyzed for total cholesterol, HDL cholesterol, triglycerides and glucose. Subjects also completed a questionnaire on miscellaneous health behaviours (exercise, smoking, alcohol consumption). Hierarchical linear regression analyses were used to investigate associations between seasonality and objective health measurements, while binary logistic regression was used for analysing associations between seasonality and health behaviours. Analyses were adjusted for sociodemographic factors, month of questionnaire completion and sleep duration. Seasonality was positively associated with high waist-hip-ratio, BMI, triglyceride levels, and in men high total cholesterol. Seasonality was negatively associated with HDL cholesterol. In women seasonality was negatively associated with prevalence of exercise and positively associated with daily cigarette smoking.

Conclusions/Significance

High seasonality was associated with objective health risk factors and in women also with health behaviours associated with an increased risk for cardiovascular disease.     

Reduced Pain and Inflammation in Juvenile and Adult Rats Fed a Ketogenic Diet

The ketogenic diet is a high-fat, low-carbohydrate regimen that forces ketone-based rather than glucose-based cellular metabolism. Clinically, maintenance on a ketogenic diet has been proven effective in treating pediatric epilepsy and type II diabetes, and recent basic research provides evidence that ketogenic strategies offer promise in reducing brain injury. Cellular mechanisms hypothesized to be mobilized by ketone metabolism and underlying the success of ketogenic diet therapy, such as reduced reactive oxygen species and increased central adenosine, suggest that the ketolytic metabolism induced by the diet could reduce pain and inflammation. To test the effects of a ketone-based metabolism on pain and inflammation directly, we fed juvenile and adult rats a control diet (standard rodent chow) or ketogenic diet (79% fat) ad libitum for 3–4 weeks. We then quantified hindpaw thermal nociception as a pain measure and complete Freund''s adjuvant-induced local hindpaw swelling and plasma extravasation (fluid movement from the vasculature) as inflammation measures. Independent of age, maintenance on a ketogenic diet reduced the peripheral inflammatory response significantly as measured by paw swelling and plasma extravasation. The ketogenic diet also induced significant thermal hypoalgesia independent of age, shown by increased hindpaw withdrawal latency in the hotplate nociception test. Anti-inflammatory and hypoalgesic diet effects were generally more robust in juveniles. The ketogenic diet elevated plasma ketones similarly in both age groups, but caused slowed body growth only in juveniles. These data suggest that applying a ketogenic diet or exploiting cellular mechanisms associated with ketone-based metabolism offers new therapeutic opportunities for controlling pain and peripheral inflammation, and that such a metabolic strategy may offer significant benefits for children and adults.     

Analysis of a Dengue Model with Vertical Transmission and Application to the 2014 Dengue Outbreak in Guangdong Province,China

There is evidence showing that vertical transmission of dengue virus exists in Aedes mosquitoes. In this paper, we propose a deterministic dengue model with vertical transmission in mosquitoes by including aquatic mosquitoes (eggs, larvae and pupae), adult mosquitoes (susceptible, exposed and infectious) and human hosts (susceptible, exposed, infectious and recovered). We first analyze the existence and stability of disease-free equilibria, calculate the basic reproduction number and discuss the existence of the disease-endemic equilibrium. Then, we study the impact of vertical transmission of the virus in mosquitoes on the spread dynamics of dengue. We also use the model to simulate the reported infected human data from the 2014 dengue outbreak in Guangdong Province, China, carry out sensitivity analysis of the basic reproduction number in terms of the model parameters, and seek for effective control measures for the transmission of dengue virus.     

Intensity of Bud Dormancy in Douglas-fir and Its Relation to Scale Removal and Rooting Ability

Uniform 1- or 2-year-old rooted cuttings of 3 Douglas-fir, Pseudotsuga menziesii (Mirb.) Franco, clones were grown under natural conditions in containers from July 1, 1971 to February 15, 1972. At 2-week intervals, plants from this natural temperature and daylength environment were moved into controlled, long day (LD-18 h) and short day (SD-9 h) environments to measure the intensity of bud dormancy from its inception to termination based on number of days to bud break and percentage of expanding buds on a given date. Growth responses to bud scale removal were also helpful in describing the degree and nature of bud dormancy. The cessation of initiatory activity at the bud apex, reflected in the needle number of the subsequent growth flush, corresponded to a September peak of bud dormancy based on the number of days to bud break in the LD environment. Similarly, the cold requirement for breaking bud dormancy was measurable in the SD environment. The use of such rest intensity indices is illustrated in the close relationship established between bud dormancy development and stem cutting rooting ability.     

Phylogenetic Analysis of the Dengue Virus Strains Causing the 2019 Dengue Fever Outbreak in Hainan,China

Dengue virus is an arthropod-borne pathogen that is transmitted to humans primarily by Aedes spp.mosquitos,causing the acute infectious disease,dengue fever (DF).Until 2019,no dengue outbreak had been reported in Hainan Province for over20 years.However,in early September of 2019,an increasing number of infected cases appeared and the DF outbreak lasted for over one month in Haikou City,Hainan Province.In our study,we collected 97 plasma samples from DF patients at three hospitals,as well as 1585 mosquito larvae samples from puddles in different areas of Haikou.There were 49(50.5%) plasma samples found to be strongly positive and 9 (9.3%) plasma samples were weakly positive against the NS1 antigen.We discovered DENV both in the patient's plasma samples and mosquito larvae samples,and isolated the virus from C6/36 cells inoculated with the acute phase serum of patients.Phylogenetic analysis revealed that the new strains were the most closely related to the epidemic strain in the southern regions of China,belonging to lineage IV,genotype I,DENV-1.Compared to the seven closest strains from neighboring countries and provinces,a total of 18 amino acid mutations occurred in the coding sequences (CDS) of the new isolated strain,DENV1 HMU-HKU-2.Our data shows that dengue virus is re-emerged in Hainan,and pose new threats for public health.Thus regular molecular epidemiological surveillance is necessary for control and prevention of DENV transmission.     

Altered Pain Sensitivity in Elderly Women with Chronic Neck Pain

Background

Age-related changes occur in both the peripheral and central nervous system, yet little is known about the influence of chronic pain on pain sensitivity in older persons. The aim of this study was to investigate pain sensitivity in elders with chronic neck pain compared to healthy elders.

Methods

Thirty elderly women with chronic neck pain and 30 controls were recruited. Measures of pain sensitivity included pressure pain thresholds, heat/cold pain thresholds and suprathreshold heat pain responses. The pain measures were assessed over the cervical spine and at a remote site, the tibialis anterior muscle.

Results

Elders with chronic neck pain had lower pressure pain threshold over the articular pillar of C5-C6 and decreased cold pain thresholds over the cervical spine and tibialis anterior muscle when compared with controls (p < 0.05). There were no between group differences in heat pain thresholds and suprathreshold heat pain responses (p > 0.05).

Conclusion

The presence of pain hypersensitivity in elderly women with chronic neck pain appears to be dependent on types of painful stimuli. This may reflect changes in the peripheral and central nervous system with age.