High frequency of hepatitis B virus infection in patients with beta-thalassemia receiving multiple transfusions

BACKGROUND AND OBJECTIVES: Hepatitis B virus (HBV) may occasionally be transmitted through transfusion of blood units that are hepatitis B surface antigen (HBsAg) negative but HBV DNA positive. Children with beta-thalassemia are particularly susceptible to HBV because they receive multiple blood transfusions. These children have high infection rates despite vaccination against HBV. Post-vaccination infections may be a result of viruses harbouring surface (S)-gene mutations (e.g. G587A) in a region critical for reactivity to antibody to hepatitis B surface antigen (anti-HBs). The true prevalence of HBV in individuals with beta-thalassemia has not been studied previously. PATIENTS AND METHODS: Seventy patients with beta-thalassemia (median age 6 years; range 8 months to 22 years; 49 male), who had received seven to 623 (median 61) units of blood each and three doses (10/20 micro g) of HBV vaccine (Engerix B) before presentation to us, were included in the study; 50 of the 70 patients had received transfusions prior to vaccination. Enzyme-linked immunoassay for serological markers [HBsAg, antibody to hepatitis B core antigen (anti-HBc) and quantitative anti-HBs] and polymerase chain reaction (PCR) followed by Southern hybridization for molecular detection of hepatitis B, was performed on all samples. The PCR-amplified product was cloned, sequenced and the nucleotide and deduced amino acid sequences for the HBV S and polymerase (P) genes were analysed for mutations. RESULTS: Four of 70 (5.7%) individuals with beta-thalassemia were HBsAg positive and 14 (20%) were anti-HBc positive. The prevalence of serological markers increased with number of transfusions (P < 0.01). Of 70 patients, 53 (75.7%) had an anti-HBs titre of > 10 IU/l following vaccination and 17 (24.3%) were non-responders (< 10 IU/l); 22 (31.4%) of the 70 were DNA positive. The frequency of HBV infection in beta-thalassemia was similar in vaccine responders and non-responders. The virus was of subtype ayw (genotype D) in the five DNA-positive samples in which a 388-nucleotide region of the S gene was sequenced. Mutations occurred at 13 positions in the S gene and at 10 positions in the P gene. Hydrophobicity plots revealed differences in amino acid regions 117-165 and 195-211. Some of these amino acid substitutions coincided with the putative cytotoxic T-lymphocyte epitopes of both S and P proteins. CONCLUSIONS: A high frequency of HBV infection was seen using molecular methods in thalassemic patients. The frequency of infection was similar in vaccine responders and non-responders. A number of mutations were observed in the S gene, which could have implications for viral replication as well as virus-host cell interaction.     

A Medicare-Associated Spike in U.S. Cancer Rates at Age 65, 2000–2010

Age 65 represents a transition point where most U.S. residents begin Medicare coverage. We examined whether or not delays in medical care near this age extend to cancer diagnosis. We calculated single-year-of-age cancer incidence rates by site and stage for the most common cancer sites (i.e., prostate, female breast, lung, and colorectal) for the 2000–2010 period using data from the SEER 18 registries, and we used Poisson regression to identify a possible age-65 effect. The analysis was repeated on comparable Canadian data. Cancer rates at age 65 were found to be as much as 15% above expected in the U.S. data, with the age-65 effect strongly associated with site- and stage-specific survival. A smaller association was seen in the Canadian data. We found strong evidence that diagnosis of less severe cancers spikes at age 65. Delay of medical care prior to this age has complex policy implications.The 65th birthday is a major life milestone for many Americans. It corresponds to the age when nearly all become eligible for health-care coverage through Medicare, when many begin receiving Social Security benefits, and when many choose to retire. This age boundary has been shown to have profound effects on health and health-care utilization. For example, rates of medical screening, diagnosis, and treatment for conditions that are low urgency, asymptomatic, and reimbursable by Medicare are found at much higher levels among those aged 65 years than those aged 64 years.^1–3 It has been suggested that this phenomenon is driven by the low-cost “Welcome to Medicare” physical examination instituted in 2005, but too few people have taken advantage of this feature for it to explain much of the difference.⁴In contrast, rates of “nondeferrable admissions,” defined as conditions where hospital admission rates through emergency departments do not diminish on weekends, show no change at age 65 years.⁵ For those who are uninsured or underinsured, there are clear financial incentives to postpone nonurgent medical encounters until Medicare is available. The effect is too large, however, to be explained by the behavior of the uninsured and underinsured alone. Even some people who are fully insured postpone treatment until age 65 years, either because of the perception that Medicare is a more generous health-care plan than other insurance plans or because postponing is more convenient.⁵ Recovering from a hip replacement while retired, for example, may be more practical than attempting to do so while employed.None of the existing research on pent-up demand for Medicare has, to our knowledge, specifically considered cancer incidence. We hypothesized that cancer should follow the same pattern as seen for other medical conditions. Specifically, screen-detected, asymptomatic, nonlethal tumors should show an unusually high incidence rate at age 65 years relative to other ages, while advanced-stage, low-survival tumors should show no difference. If correct, this observation should inform the current discussion regarding the extent to which certain cancers are being overdiagnosed and overtreated as a consequence of aggressive screening,⁶ as the Medicare program may be unwittingly bearing an undue share of the cost of such treatment. Conversely, underdiagnosis and undertreatment of those approaching 65 years of age may also be unduly shortening life spans among this group.We measured the elevation in cancer rates at age 65 years above what would be expected based on the otherwise smooth trend between ages 55 and 75 years. We considered prostate, female breast, lung, and colorectal cancers—the four most common cancer sites—which accounted for approximately 54% of all incident cases in the United States during the 2000–2010 period. Each of these cancers is detectable through screening, although at the time of writing only colorectal cancer screening for those aged 50–75 years was unequivocally endorsed by the U.S. Preventive Services Task Force (USPSTF).⁷ Breast cancer screening for women aged 50–74 years is generally recommended, but the guidelines for women older than 40 years of age are currently under review.^8,9 Lung cancer screening is recommended only for current or recent heavy smokers aged 55–80 years,¹⁰ and prostate cancer screening is not recommended at all.¹¹ We further investigated the relationship between the age-65 effect and the severity of the cancer, as measured by five-year survival. Finally, we compared the results from the United States with equivalent results from Canada, where no change in health-care insurance status occurs at age 65, but where 65 is also a popular retirement age.     

Evaluation of retinopathy of prematurity screening in reverse Kangaroo Mother Care: a pilot study

Purpose

To evaluate retinopathy of prematurity (ROP) screening practice in reverse Kangaroo Mother Care (R-KMC) with respect to stress and pain to the infant.

Methods

In a pilot study we evaluated ROP screening practice in R-KMC in 20 babies at risk of ROP. The R-KMC differed from the conventional KMC with respect to the baby position where the baby lay supine on mother''s chest. With the mother lying supine and the baby in R-KMC position, screening examinations were done with indirect ophthalmoscope. The outcome measures included stress (quantified by pulse, respiration, and oxygen saturation) and pain to the baby by observing facial expression (eye squeezing, crying, and brow bulge). The heart rate, respiratory rate, and SpO2 (%) were compared before and immediately after the procedure using paired t-test.

Result

Mean (±SD) gestational age and birth weight were 30.8±2.3 weeks and 1362.5±253.9 g, respectively. During examination in R- KMC position 8 babies (40%) were completely relaxed (no eye squeezing and crying), 10 (50%) were partially relaxed (no brow bulge) and 2 babies (10%) were not relaxed. A change in heart and respiration rate both by 10 per minute was recorded in 12 (60%) and 10 (50%) babies, respectively. Five babies (25%) had reduction in blood oxygen concentration below 92%. The majority of the mothers (19 of 20) were relaxed.

Conclusion

ROP screening in R-KMC can be a baby friendly screening practice with respect to stress and pain to the infant and needs further evaluation in a larger cohort.     

Diastereoselective synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction and in vitro anticancer studies

The development of concise methods for the synthesis of small functionalised spirocyclic molecules is important in the search of new bioactive molecules. To contribute this, here we represent a diastereoselective oxa-hetero-Diels–Alder reaction for the synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives and studied their in vitro anticancer activities. Using previously less explored cyclic ketone i.e. indane-1,3-dione and 3-vinyl-2H-chromene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between “drug-like” molecules and natural products. Various spiro indanone fused pyrano[3,2-c]chromene derivatives were synthesized regiospecifically bearing a quaternary stereocenter in high yields (up to 85%) with excellent diastereoselectivity in toluene using 4 Å MS as additive under reflux condition at 120 °C. In vitro cytotoxic studies of these compounds against MCF-7 (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer), MD-MB-231(Breast cancer) cell lines were evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide} assay in vitro. The screening results revealed that many of the compounds are showing moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed potent inhibitory activities in comparison to the commercial anticancer drug 5-fluorouracil (5-FU). Among the series, compound 3′c showed most potent cytotoxicity (15.0–27.5 μM) in three cancer cell lines (MCF-7, HCT-116 and MD-MB-231).

Synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction has been demonstrated and evaluated for their in vitro anticancer activity.     

Non‐invasive left ventricular myocardial work indices in healthy adolescents at rest

Global myocardial work (GMW) provides a metric of left ventricular (LV) function and energy consumption. Its non-invasive assessment by echocardiography correlates with invasive measures and normal values have been reported in healthy adults. We aimed to establish normal values in a healthy adolescent population. Fifty-two healthy adolescents (mean age?=?14.5?±?2.0 years, range 11–19 years, 62% male) with normal echocardiograms were included. Brachial cuff blood pressure was obtained immediately following apical imaging in the supine position. Post-processing of echocardiograms for speckle tracking strain measurement and derivation of global myocardial work indices from LV pressure–strain loops was performed. The mean global work index (GWI) was 1802.0?±?264.4 mmHg% with mean global work efficiency of 95.5?±?1.1%. The mean global constructive work (GCW) was 2054.5?±?297.3 mmHg%, and the mean global wasted work 83.8?±?28.1 mmHg%. On multivariable analysis, there were significant associations between both GWI and GCW with systolic blood pressure (β coefficient?=?0.57, p?<?0.001; β coefficient?=?0.67, p?<?0.001 respectively) and LV global longitudinal strain (GLS) (β coefficient = ? 0.56, p?<?0.001; β coefficient = ? 0.52, p?<?0.001 respectively). There were no associations with any of the work indices with age, sex, body surface area, heart rate or LV ejection fraction. This study provides echocardiographic reference ranges for non-invasive indices of GMW in normal adolescents.

     

Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes

Background

Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion.

Insulin,proinsulin, proinsulin:insulin ratio,and the risk of developing type 2 diabetes mellitus in women

PURPOSE: To assess the associations among baseline levels of fasting insulin and proinsulin, proinsulin:insulin ratio, and the development of type 2 diabetes mellitus in apparently healthy middle-aged women. METHODS: In a nested case-control study involving a nationwide cohort of 27,628 participants from the Women's Health Study, 126 women with diabetes diagnosed during a 4-year follow-up period were compared with 225 age-matched controls. Fasting insulin level and proinsulin:insulin ratio were assessed in quartiles, and proinsulin level was assessed in categories (< or =4.0 pmol/L, 4.01 to 6.99 pmol/L, > or =7.0 pmol/L). The risk of developing type 2 diabetes was determined using conditional logistic regression analysis that adjusted for body mass index and other diabetes risk factors. RESULTS: Baseline insulin and proinsulin levels and proinsulin:insulin ratios were significantly higher among cases than among controls. Women with elevated insulin levels in the highest as compared with the lowest quartile were more likely to develop diabetes (odds ratio [OR] = 5.6; 95% confidence interval [CI]: 1.8 to 17.6), as were women with elevated (> or =7.0 pmol/L vs. < or =4.0 pmol/L) proinsulin levels (OR = 16.4; 95% CI: 5.8 to 46.8) and women with proinsulin:insulin ratios in the highest quartile (OR = 9.6; 95% CI: 3.1 to 30.8). Similar results were observed among women with a baseline hemoglobin A(1c) level < or =6.0%. In time-trend analyses, fasting insulin was a consistent predictor of long-term risk. Proinsulin and proinsulin:insulin ratio, although predictive throughout the study, were especially strong predictors of rapid progression to type 2 diabetes. CONCLUSION: Elevated fasting insulin and proinsulin levels and proinsulin:insulin ratio are associated with an increased risk of developing type 2 diabetes in apparently healthy middle-aged women.