Genetic variation and haplotype structures of innate immunity genes in eastern India

This study reports results of an extensive and comprehensive study of genetic diversity in 12 genes of the innate immune system in a population of eastern India. Genomic variation was assayed in 171 individuals by resequencing approximately 75kb of DNA comprising these genes in each individual. Almost half of the 548 DNA variants discovered was novel. DNA sequence comparisons with human and chimpanzee reference sequences revealed evolutionary features indicative of natural selection operating among individuals, who are residents of an area with a high load of microbial and other pathogens. Significant differences in allele and haplotype frequencies of the study population were observed with the HapMap populations. Gene and haplotype diversities were observed to be high. The genetic positioning of the study population among the HapMap populations based on data of the innate immunity genes substantially differed from what has been observed for Indian populations based on data of other genes. The reported range of variation in SNP density in the human genome is one SNP per 1.19kb (chromosome 22) to one SNP per 2.18kb (chromosome 19). The SNP density in innate immunity genes observed in this study (>3SNPskb(-1)) exceeds the highest density observed for any autosomal chromosome in the human genome. The extensive genomic variation and the distinct haplotype structure of innate immunity genes observed among individuals have possibly resulted from the impact of natural selection.     

Mitral stenosis in a girl of five years

Mitral stenosis(MS) detected below the age of 20 years is called juvenile mitral stenosis (JMS). JMS constitute 25-40 % of all cases of isolated mitral stenosis, though overall incidence of rheumatic fever and rheumatic heart disease (RHD) within mixed population is 7.5- 7.8 per thousand. The patient was 5 years old girl hailing from Modhupur, Tangail got herself admitted into CCU Mymensingh Medical College Hospital with the complaints of low grade fever, shortness of breath and also associated with failure to thrive. She was ill looking, mildly anaemic. Precordial examination revealed apex beat was in the left 5th intercostals space, tapping in nature, palpable P(2). There was left parasternal heave. 1st heart sound loud, pulmonary component of the 2nd heart sound was accentuated, opening snap with mid diastolic murmur with pre systolic accentuation. Routine blood examination reveals leucocytosis with raised ESR. C-reactive protein (CRP) and ASO titre were significantly raised. X-ray chest P/A view showing the features of mitral stenosis. Echocardiography showing MS (moderate) with pulmonary hypertension. She was treated with antibiotics and other relevant drugs and discharge with an advice for follow up and take preparation for cardiac intervention.     

Budd-Chiari syndrome

A 30 years old, non-alcoholic farmer from Trishal, Mymensingh was admitted in Mymensingh Medical College Hospital on 7 February, 2004 with the complaints of gradual swelling of abdomen, both legs and upper abdominal pain for 3 months. For the last 6 years, he was treated as a case of chronic liver disease (CLD) with spironolactone and frusemide. He was non-icteric, mildly anaemic with mild oedema, clubbing, gynaecomastia and engorged vein over anterior abdominal wall, flanks and back. Direction of venous flow was from below upward. There were mild hepatosplenomegaly, ascites and bilateral testicular atrophy. He was diagnosed as a case of Budd-Chiari Syndrome (BCS) on the basis of physical examination and it was confirmed by the findings of ultrasonography, liver scan and doppler study. The patient was managed by medical therapy alone.     

Comparative cost-effectiveness of bazedoxifene and raloxifene in the treatment of postmenopausal osteoporosis in Europe, using the FRAX algorithm

Summary

Bazedoxifene and raloxifene were evaluated in the treatment of postmenopausal osteoporosis from health economic perspective in Europe. Based on a computer-based algorithm calculating efficacy of the treatments, bazedoxifene appears to be a cost-effective strategy compared to raloxifene, particularly in patients at high fracture risk.

Introduction

The purpose of this study was to compare cost-effectiveness of bazedoxifene and raloxifene in eight European countries: Belgium, France, Germany, Ireland, Italy, Spain, Sweden, and the UK.

Methods

The Fracture Risk Assessment Tool, which is a computer-based algorithm to calculate fracture probability using clinical risk factors alone or with bone mineral density, was incorporated in a Markov Tunnel model to evaluate cost-effectiveness of bazedoxifene 20 or 40 mg vs. raloxifene 60 mg in postmenopausal osteoporotic women. The efficacy of bazedoxifene and raloxifene for vertebral and non-vertebral fractures was measured as a function of the 10-year probability of a major osteoporotic fracture. The model estimated the incremental cost-effectiveness ratio and net monetary benefit (NMB) from a healthcare perspective, given the willingness to pay €30,000.

Results

In postmenopausal osteoporotic women, bazedoxifene was a cost saving strategy compared to raloxifene in the countries studied. The median NMB of bazedoxifene compared to raloxifene increased monotonically with the 10-year fracture probability. In general, the median NMB became greater than 0 in women with 10-year probabilities of a major osteoporotic fracture between 5 and 10 % or above. The impact on results by varying the assumptions in the model was examined in sensitivity analysis.

Conclusion

Bazedoxifene appears to be a cost-effective strategy compared to raloxifene for the treatment of postmenopausal osteoporotic women in Europe, particularly in patients at high fracture risk.     

The role of π-linkers and electron acceptors in tuning the nonlinear optical properties of BODIPY-based zwitterionic molecules

Intramolecular charge transfer process can play a key role in developing strong nonlinear optical (NLO) response in a molecule for technological application. Herein, two series of boron dipyrromethene (BODIPY)-based push–pull systems have been designed with zwitterionic donor–acceptor groups, and their NLO properties have been evaluated using a density functional theory-based approach. Different π-conjugated linkers and electron acceptor groups were used to understand their roles in tuning the NLO properties. The molecules were analyzed through HOMO–LUMO gaps, frontier molecular orbitals, polarizabilities, hyperpolarizabilities, Δr indices, transition dipole moment densities, ionization potentials, electron affinities and reorganization energies for holes and electrons. These observations correlated well with the computed absorption spectra of the molecules. It is found that with the introduction of different π-linkers in the molecule, planarity is maintained and the HOMO–LUMO gap is systematically decreased, which leads to a large NLO response. It was noted that the electronic absorption wavelength maxima were found in the near-infrared region (934–1650 nm). The results show that compared to the pyridinium acceptor group, the imidazolium acceptor group in the BODIPY systems amplifies the NLO response to a larger extent. It is also observed that the BODIPY-based dye with an imidazolium acceptor and thienothiophene π-linker shows the highest first hyperpolarizability value of 3194 × 10⁻³⁰ esu. Furthermore, the charge transfer occurs in the z-direction, as the z-component of the first hyperpolarizability is the dominant factor in this system. Here, the designed molecules show a characteristic reorganisation energy value, which is a deciding factor in the rate of hole/electron transport for favourable intermolecular coupling. As a whole, this theoretical work highlights that π-conjugated linkers and electron acceptor groups can be used judiciously to design new molecular systems for optoelectronic applications.

BODIPY-based zwitterionic molecules with pyridinium and imidazolium electron acceptors and thienothiophene π-linkers reveal significant first hyperpolarizability.     

Predictors of attendance at specialized survivor clinics in a population-based cohort of adult survivors of childhood cancer

Purpose

The purpose of the present study is to determine predictors of attendance at a network of publicly funded specialized survivor clinics by a population-based cohort of adult survivors of childhood cancer.

Methods

We conducted a retrospective study linking data on eligible patients identified in a provincial pediatric cancer registry with health administrative databases to determine attendance at five specialized survivor clinics in the Canadian province of Ontario between 1999 and 2012. Eligible survivors were treated for cancer at ≤18 years between 1986 and 2005, had survived ≥5 years from their most recent pediatric cancer event, and contributed ≥1 year of follow-up after age 18 years. We assessed the impact of cancer type, treatment intensity, cumulative chemotherapy doses, radiation, socioeconomic status, distance to nearest clinic, and care from a primary care physician (PCP) on attendance using recurrent event multivariable regression.

Results

Of 7482 children and adolescents treated for cancer over the study period, 3972 were eligible for study inclusion, of which 3912 successfully linked to administrative health data. After a median of 7.8 years (range 0.2–14.0) of follow-up, 1695/3912 (43.3 %) had attended at least one adult survivor clinic visit. Significantly increased rates of attendance were associated with female gender, higher treatment intensity, radiation, higher alkylating agent exposure, higher socioeconomic status, and an annual exam by a PCP. Distance significantly impacted attendance with survivors living >50 km away less likely to attend than those living within 10 km (relative rate 0.77, p?=?0.003).

Conclusion

Despite free access to survivor clinics, the majority of adult survivors of childhood cancer do not attend.

Implications for Cancer Survivors

Alternate models of care need to be developed and assessed, particularly for survivors living far from a specialized clinic and those at lower risk of developing late effects.

     

Long-term outcomes of women with large DCIS lesions treated with breast-conserving therapy

Breast Cancer Research and Treatment -     

Treatment patterns and outcomes in adolescents and young adults with nodular lymphocyte-predominant Hodgkin lymphoma: an IMPACT cohort study

We leveraged population-based clinical and healthcare data to identify treatment patterns and long-term outcomes among adolescents and young adults (AYA) with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). All Ontario, Canada, AYA aged 15–21 years at diagnosis with NLPHL between 1992 and 2012 were identified, and their detailed clinical data were collected. Linkage to healthcare databases identified additional events (subsequent malignant neoplasms [SMN], relapses and deaths). Event-free survival (EFS) and overall survival (OS) were compared by locus of care (adult vs. paediatric) and predictors of outcomes determined. Of 1014 AYA with Hodgkin lymphoma, 54 (5.3%) had NLPHL; 15 (27.8%) were treated at a paediatric centre. No paediatric centre patient received radiation only versus 16 (41.0%) of adult centre patients. Excision only was more common in paediatric centres (p < 0.001). The 20-year EFS and OS rates were 82.9% ± 5.2% and 100% respectively. Advanced stage (hazard ratio: 4.9, 95% CI: 1.3–18.4; p = 0.02) was associated with inferior EFS. Although the 25-year cumulative incidence of SMN was 19.3% ± 9.6% for the entire cohort, there were no SMN among the patients treated with excision only. AYA with NLPHL have outstanding long-term survival. Resection alone was rare outside of paediatric institutions but associated with excellent outcomes. Given substantial SMN risks, chemotherapy-sparing and radiation-sparing strategies for appropriate subsets of patients are warranted.     

Morbidity and healthcare use among mothers of children with cancer: A population-based study

Background

The impact of a child's cancer diagnosis on subsequent maternal physical health is unclear.

Methods

We identified all Ontario children diagnosed less than 18 years with cancer between 1992 and 2017. Linkage to administrative databases identified mothers who were matched to population controls. We identified physical health conditions, acute healthcare use, and preventive healthcare use through validated algorithms using healthcare data, and compared them between exposed (child with cancer) and unexposed mothers. Predictors of health outcomes were assessed among exposed mothers.

Results

We identified 5311 exposed mothers and 19,516 matched unexposed mothers. For exposed mothers, median age at last follow-up was 48 years, (interquartile range: 42–53). Exposed mothers had an increased risk of cancer (hazard ratio [HR] 1.2, 95% confidence interval [95% CI]: 1.0–1.5, p = .03), but not of any other adverse physical outcomes or of increased acute healthcare use. Exposed mothers were more likely to receive influenza vaccinations (odds ratio 1.4, 95% CI: 1.3–1.5, p < .0001), and underwent cancer screening at the same rate as unexposed mothers. Among exposed mothers, bereavement was associated with a subsequent increased risk of cancer (HR 1.7, 95% CI: 1.2–2.5, p = .004) and death (HR 2.2, 95% CI: 1.2–4.1, p = .01).

Conclusion

Mothers of children with cancer are at increased risk of developing cancer, but not of other adverse physical health outcomes, and were equally or more likely to be adherent to preventive healthcare practices. Bereaved mothers were at increased risk of subsequent cancer and death. Interventions targeting specific subpopulations of mothers of children with cancer or focused on screening for specific cancers may be warranted.