The effects of tertiary and quaternary infections on the epidemiology of dengue

This is the final version of the article. Available from Public Library of Science via the DOI in this record.The epidemiology of dengue is characterised by irregular epidemic outbreaks and desynchronised dynamics of its four co-circulating virus serotypes. Whilst infection by one serotype appears to convey life-long protection to homologous infection, it is believed to be a risk factor for severe disease manifestations upon secondary, heterologous infection due to the phenomenon of Antibody-Dependent Enhancement (ADE). Subsequent clinical infections are rarely reported and, since the majority of dengue infections are generally asymptomatic, it is not clear if and to what degree tertiary or quaternary infections contribute to dengue epidemiology. Here we investigate the effect of third and subsequent infections on the transmission dynamics of dengue and show that although the qualitative patterns are largely equivalent, the system more readily exhibits the desynchronised serotype oscillations and multi-annual epidemic outbreaks upon their inclusion. More importantly, permitting third and fourth infections significantly increases the force of infection without resorting to high basic reproductive numbers. Realistic age-prevalent patterns and seroconversion rates are therefore easier reconciled with a low value of dengue's transmission potential if allowing for more than two infections; this should have important consequences for dengue control and intervention measures.This work was funded by the BBSRC (PSW) and the Royal Society (MR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Case report: Thoracoscopic repair of renal ectopia associated with congenital diaphragmatic hernia: Report of two cases

Renal ectopia is a rare anomaly which may occur due to an abnormal ascent of the kidney. It is usually  asymptomatic and does not require treatment. Intrathoracic renal ectopia with concomitant congenital diaphragmatic hernia (CDH) is extremely rare. All symptomatic CDH cases must be treated with open or thoracoscopic repair. During plication of the diaphragm, care must be taken to avoid renal injury. Following, we present two rare variants of CDH with concomitant renal ectopia managed thoracoscopically.  Postoperative recovery was uneventful. Doppler ultrasound study performed one month after surgery confirmed normal vascularity of the kidneys and the absence of urinary outflow obstruction.KEYWORDS: Congenital diaphragmatic hernia; Renal ectopia; Thoracoscopic repai

Allele mining in β-lactoglobulin gene of Capra hircus

β-Lactoglobulin (β-LG) genetic polymorphisms are important and well known due to their effects on quantitative traits and technological properties of milk. At the DNA level, polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) allows for the detection of unknown polymorphisms at β-LG loci. Here we describe the usefulness of the PCR-SSCP technique for β-LG typing. In the present study, we amplified and sequenced the part of promoter region and all the seven exons containing the entire coding and untranslated region for the β-lactoglobulin gene in best dairy goat breeds of India namely: Jamunapari and Jakhrana. Nine polymorphisms were detected, one in the l promoter region, four in the introns and four in the exons of the β-lactoglobulin gene. All polymorphisms were single nucleotide substitutions. The polymorphisms in the coding region did not produce any amino acid change.Key words: β-Lactoglobulin gene, dairy goats, polymorphism, single nucleotide polymorphism (SNP), single strand conformational polymorphism (SSCP)

ASCORE: an up-to-date cardiovascular risk score for hypertensive patients reflecting contemporary clinical practice developed using the (ASCOT-BPLA) trial data.

A number of risk scores already exist to predict cardiovascular (CV) events. However, scores developed with data collected some time ago might not accurately predict the CV risk of contemporary hypertensive patients that benefit from more modern treatments and management. Using data from the randomised clinical trial Anglo-Scandinavian Cardiac Outcomes Trial-BPLA, with 15 955 hypertensive patients without previous CV disease receiving contemporary preventive CV management, we developed a new risk score predicting the 5-year risk of a first CV event (CV death, myocardial infarction or stroke). Cox proportional hazard models were used to develop a risk equation from baseline predictors. The final risk model (ASCORE) included age, sex, smoking, diabetes, previous blood pressure (BP) treatment, systolic BP, total cholesterol, high-density lipoprotein-cholesterol, fasting glucose and creatinine baseline variables. A simplified model (ASCORE-S) excluding laboratory variables was also derived. Both models showed very good internal validity. User-friendly integer score tables are reported for both models. Applying the latest Framingham risk score to our data significantly overpredicted the observed 5-year risk of the composite CV outcome. We conclude that risk scores derived using older databases (such as Framingham) may overestimate the CV risk of patients receiving current BP treatments; therefore, 'updated' risk scores are needed for current patients

Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial.

BACKGROUND AND AIMS: Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment. METHODS: Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes. RESULTS: Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality. CONCLUSIONS: Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period

Spontaneous corneal melting in pregnancy: a case report

<p>Abstract</p> <p>Background</p> <p>To report a case of spontaneous corneal melting in pregnancy. We reviewed the literature on corneal melting and the effect of pregnancy on cornea and collagen containing tissues.</p> <p>Case presentation</p> <p>A 29-year-old woman who underwent radial keratotomy in both eyes followed by trabeculectomy in her left eye developed corneal melting in the same eye, in her seventh month of pregnancy. Despite screening, no infectious or immune mediated condition could be identified. She was managed conservatively with cyanoacrylate glue, bandage contact lens, lubricants and antibiotics.</p> <p>Conclusion</p> <p>It may not always be possible to find the underlying cause of corneal melting but the more common underlying causes should be ruled out by proper investigations. Pregnancy with its host of hormonal changes could potentially have some effect on corneal collagen leading to corneal melting in compromised corneas.</p

Sisyphus Cooling of Electrically Trapped Polyatomic Molecules

The rich internal structure and long-range dipole-dipole interactions establish polar molecules as unique instruments for quantum-controlled applications and fundamental investigations. Their potential fully unfolds at ultracold temperatures, where a plethora of effects is predicted in many-body physics, quantum information science, ultracold chemistry, and physics beyond the standard model. These objectives have inspired the development of a wide range of methods to produce cold molecular ensembles. However, cooling polyatomic molecules to ultracold temperatures has until now seemed intractable. Here we report on the experimental realization of opto-electrical cooling, a paradigm-changing cooling and accumulation method for polar molecules. Its key attribute is the removal of a large fraction of a molecule's kinetic energy in each step of the cooling cycle via a Sisyphus effect, allowing cooling with only few dissipative decay processes. We demonstrate its potential by reducing the temperature of about 10^6 trapped CH_3F molecules by a factor of 13.5, with the phase-space density increased by a factor of 29 or a factor of 70 discounting trap losses. In contrast to other cooling mechanisms, our scheme proceeds in a trap, cools in all three dimensions, and works for a large variety of polar molecules. With no fundamental temperature limit anticipated down to the photon-recoil temperature in the nanokelvin range, our method eliminates the primary hurdle in producing ultracold polyatomic molecules. The low temperatures, large molecule numbers and long trapping times up to 27 s will allow an interaction-dominated regime to be attained, enabling collision studies and investigation of evaporative cooling toward a BEC of polyatomic molecules

Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders.

Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4-16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12-0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20-1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26-0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06-0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.MR

Properties of small molecular drug loading and diffusion in a fluorinated PEG hydrogel studied by ^1H molecular diffusion NMR and ^(19)F spin diffusion NMR

R_f-PEG (fluoroalkyl double-ended poly(ethylene glycol)) hydrogel is potentially useful as a drug delivery depot due to its advanced properties of sol–gel two-phase coexistence and low surface erosion. In this study, ^1H molecular diffusion nuclear magnetic resonance (NMR) and ^(19)F spin diffusion NMR were used to probe the drug loading and diffusion properties of the R_f-PEG hydrogel for small anticancer drugs, 5-fluorouracil (FU) and its hydrophobic analog, 1,3-dimethyl-5-fluorouracil (DMFU). It was found that FU has a larger apparent diffusion coefficient than that of DMFU, and the diffusion of the latter was more hindered. The result of ^(19)F spin diffusion NMR for the corresponding freeze-dried samples indicates that a larger portion of DMFU resided in the R_f core/IPDU intermediate-layer region (where IPDU refers to isophorone diurethane, as a linker to interconnect the R_f group and the PEG chain) than that of FU while the opposite is true in the PEG–water phase. To understand the experimental data, a diffusion model was proposed to include: (1) hindered diffusion of the drug molecules in the R_f core/IPDU-intermediate-layer region; (2) relatively free diffusion of the drug molecules in the PEG-water phase (or region); and (3) diffusive exchange of the probe molecules between the above two regions. This study also shows that molecular diffusion NMR combined with spin diffusion NMR is useful in studying the drug loading and diffusion properties in hydrogels for the purpose of drug delivery applications

Tissue Harvester with Functional Valve (THFV): Shidham's device for reproducibly higher specimen yield by fine needle aspiration biopsy with easy to perform steps

BACKGROUND: Fine needle aspiration biopsy (FNAB) cytology has been a highly effective methodology for tissue diagnosis and for various ancillary studies including molecular tests. In addition to other benefits, FNAB predominantly retrieves the diagnostic loosely cohesive cells in the lesion as compared to the adjacent supporting stroma with relatively higher cohesiveness. However, FNAB procedure performed with currently available resources is highly skill dependent with inter-performer variability, which compromises its full potential as a diagnostic tool. In this study we report a device overcoming these limitations. METHODS: 'Tissue Harvester with Functional Valve' (THFV) was evaluated as part of a phase 1 National Institute of Health (NIH) research grant under Small Business Technology Transfer (STTR) Program. Working prototypes of the device were prepared. Each of the four cytopathologists with previous cytopathology fellowship training and experience in performing FNAB evaluated 5 THFV and 5 hypodermic needles resulting in 40 specimens (20 with THFV, 20 with hypodermic needles). A piece of fresh cattle liver stuffed in latex glove was used as the specimen. Based on these results a finished design was finalized. RESULTS: The smears and cell blocks prepared from the specimens obtained by THFV were superior in terms of cellularity to specimens obtained with hypodermic needles. The tissuecrit of specimens obtained with THFV ranged from 70 to 100 μl (mean 87, SD 10), compared to 17 to 30 μl (mean 24, SD 4) with conventional hypodermic needles (p < .0001, Student t-test). The technical ease [on a scale of 1 (easy) to 5 (difficult)] with THFV ranged from 1 to 2 as compared to 2 to 3 with hypodermic needles. CONCLUSION: The specimen yield with the new THFV was significantly higher when compared to hypodermic needles. Also, the FNAB procedure with THFV was relatively easier in comparison with hypodermic needles. The final version of Shidham's THFV device would improve the FNAB specimen yield by eliminating the skill factor. The increased specimen yield by this device would also facilitate wider application of FNAB specimens for various ancillary tests, including molecular tests