Surface wave across crack-tip in a lattice model.

For a triangular lattice of particles, with nearest neighbour interactions and a traction free boundary, there exists a surface wave band for out-of-plane motion. Interactions between such a surface wave and stationary crack tip in mode III are investigated. The discrete Helmholtz equation for scattered waves, that incorporates an anisotropy parameter for unequal spring constants in horizontal versus slant directions, is solved exactly. The coefficient of transmission from one crack face to another, as well as that owing to reflection on the same face, is obtained in a closed form; the same leads to an estimate of energy fraction of incident wave that is leaked at the crack tip via bulk waves. It is found, in terms of surface wave band, that the transmission coefficient attains its maximum magnitude above the mid-band while the energy leak is minimum at the upper-band limit. Besides surface wave propagation across crack tip, surface wave excitation due to incident bulk wave is also discussed. This article is part of the theme issue 'Wave generation and transmission in multi-scale complex media and structured metamaterials (part 1)'.

Prevalence and Pregnancy Outcomes of Intrahepatic Cholestasis of Pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy is a common pregnancy-specific liver disease associated with increased risk of adverse fetal and maternal outcomes. We sought to determine its prevalence, risk factors and feto-maternal outcomes. METHODS: A retrospective review of data of 164 pregnant women diagnosed with intrahepatic cholestasis of pregnancy at Chitwan Medical College, Nepal from August 2018 to September 2020 was done. Socio-demographic data, clinic-laboratory profile and feto-maternal outcomes were obtained from clinical audit books and electronic records. A multivariate logistic regression analysis was used to evaluate the predictors of adverse neonatal outcome. RESULTS: The prevalence of intrahepatic cholestasis of pregnancy was 2.5% (164 out of 6539 deliveries). The mean age was 27.5 ± 4.4 years and 51.2% were multigravida. The preterm delivery rate was 15.2% and Caesarean delivery rate was 69.5%. 22% of the neonates needed intensive care admission out of which Respiratory Distress Syndrome or Transient Tachypnea of Newborn was seen in half of them. There were 2 cases of Intrauterine Fetal Death. In multivariate analysis, delivery <34 weeks of gestation was only found to be a significant independent predictor of adverse neonatal outcome Conclusion: The prevalence of intrahepatic cholestasis of pregnancy among pregnant women is significant in our setting which is associated with adverse fetal outcome. Early diagnosis and timely intervention is necessary in order to reduce associated perinatal morbidity.

Rheumatic Heart Disease among Pregnant Women with Cardiac Diseases in a Tertiary Care Center of Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: Cardiac disease in pregnancy is a major cause of maternal mortality and morbidity in women, particularly in resource limited countries like Nepal. Rheumatic Heart Disease is the commonest cardiac disease complicating pregnancy. There is very limited data and evidence from Nepal regarding rheumatic heart disease complicating the pregnancy. The study aims to find out the prevalence of rheumatic heart disease among cardiac disease patients in a tertiary care hospital. METHODS: A descriptive cross-sectional study was conducted among 41 women with cardiac disease who delivered babies at Chitwan Medical College from 1st January 2018 to 31st December 2019, after taking ethical approval from the Institutional Review Committee. A convenient sampling method was used. Statistical Package for the Social Sciences was used for data analysis. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. RESULTS: Among 41 pregnant women with cardiac disease, 32 (78%) (95% Confidence Interval = 65.32-90.68) had rheumatic heart disease. The mean age of the affected pregnant women was 24.9±4.49 years. Out of 32 patients with rheumatic heart disease, postpartum haemorrhage was the most common maternal complication 5 (15.6%) followed by hypertension 4 (9.7%). CONCLUSIONS: Rheumatic Heart Disease was highly common among pregnant women with cardiac disease.

Maternal and fetal characteristics and causes of stillbirth in a tertiary care hospital of Nepal: secondary analysis of registry-based surveillance data.

OBJECTIVES: Stillbirth is one of the vital indicators of quality care. This study aimed to determine maternal-fetal characteristics and causes of stillbirth in Nepal. DESIGN: Secondary analysis of single-centred registry-based surveillance data. SETTING: The study was conducted at the Department of Obstetrics and Gynecology, Chitwan Medical College Teaching Hospital, a tertiary care hospital located in Bharatpur, Nepal. PARTICIPANTS: All deliveries of intrauterine fetal death, at or beyond 22 weeks' period of gestation and/or birth weight of 500 g or more, conducted between 16 July 2017 and 15 July 2019 were included in the study. MAIN OUTCOME MEASURES: The primary outcome measure of this study was stillbirth, and the secondary outcome measures were maternal and fetal characteristics and cause of stillbirth. RESULTS: Out of 5282 institutional deliveries conducted over 2 years, 79 (1.5%) were stillbirths, which gives the stillbirth rate of 15 per 1000 births. Of them, the majority (75; 94.9%) were vaginal delivery and only four (5.1%) were caesarean section (p<0.0001). The proportion of the macerated type of stillbirth was more than that of the fresh type (58.2% vs 41.8%; p=0.13). Only half of the mothers who experienced stillbirth had received antenatal care. While the cause of fetal death was unknown in one-third of cases (31.6%; 25/79), among likely causes, the most common was maternal hypertension (29.1%), followed by intrauterine infection (8.9%) and fetal malpresentation (7.6%). Four out of 79 stillbirths (5%) had a birth defect. CONCLUSION: High rate of stillbirths in Nepal could be due to the lack of quality antenatal care. The country's health systems should be strengthened so that pregnancy-related risks such as maternal hypertension and infections are identified early on. Upgrading mothers' hygiene and health awareness is equally crucial in reducing fetal deaths in low-resource settings.

Wave scattering on lattice structures involving an array of cracks.

Scattering of waves as a result of a vertical array of equally spaced cracks on a square lattice is studied. The convenience of Floquet periodicity reduces the study to that of scattering of a specific wave-mode from a single crack in a waveguide. The discrete Green's function, for the waveguide, is used to obtain the semi-analytical solution for the scattering problem in the case of finite cracks whereas the limiting case of semi-infinite cracks is tackled by an application of the Wiener-Hopf technique. Reflectance and transmittance of such an array of cracks, in terms of incident wave parameters, is analysed. Potential applications include construction of tunable atomic-scale interfaces to control energy transmission at different frequencies.

Scattering on a square lattice from a crack with a damage zone.

A semi-infinite crack in an infinite square lattice is subjected to a wave coming from infinity, thereby leading to its scattering by the crack surfaces. A partially damaged zone ahead of the crack tip is modelled by an arbitrarily distributed stiffness of the damaged links. While an open crack, with an atomically sharp crack tip, in the lattice has been solved in closed form with the help of the scalar Wiener-Hopf formulation (Sharma 2015 SIAM J. Appl. Math., 75, 1171-1192 (doi:10.1137/140985093); Sharma 2015 SIAM J. Appl. Math. 75, 1915-1940. (doi:10.1137/15M1010646)), the problem considered here becomes very intricate depending on the nature of the damaged links. For instance, in the case of a partially bridged finite zone it involves a 2 × 2 matrix kernel of formidable class. But using an original technique, the problem, including the general case of arbitrarily damaged links, is reduced to a scalar one with the exception that it involves solving an auxiliary linear system of N × N equations, where N defines the length of the damage zone. The proposed method does allow, effectively, the construction of an exact solution. Numerical examples and the asymptotic approximation of the scattered field far away from the crack tip are also presented.

Discrete scattering by a pair of parallel defects.

Scattering of a time-harmonic anti-plane shear wave due to either a pair of crack tips or a pair of rigid constraint tips on square lattice is considered. The two problems correspond to the so-called zero-offset case of scattering due to a pair of identical Sommerfeld screens. The peculiar structural symmetry allows the reduction of coupled equations to two scalar Wiener-Hopf equations and a total of four geometrically reduced problems on lattice half-plane. Exact solution of each problem for incidence from the bulk lattice, as well as from an associated lattice waveguide, is constructed. A suitable superposition of the four expressions is used to construct the solution of the main problem. The discrete paradigm involving the wave mode incident from the waveguide is relevant for modern applications where an investigation of mechanisms of electronic and thermal transport at nanoscale remains an interesting problem. This article is part of the theme issue 'Modelling of dynamic phenomena and localization in structured media (part 2)'.

A community-based knowledge, attitude, and practice survey on rabies among cattle owners in selected areas of Bhutan.

Rabies remains a disease of significant zoonotic and economic concern in rabies endemic areas of Bhutan. Rabies outbreaks in livestock threaten the livelihoods of subsistence farming communities and pose a potential public health threat. As a part of identifying approaches to prevent rabies in cattle, a Knowledge, Attitude, and Practice (KAP) survey was conducted among cattle owners in selected rural areas of the southern rabies high-risk zone and low-risk zone in eastern Bhutan. Between March and April 2017, 562 cattle owners (281 in the east and 281 in the south) were interviewed using a questionnaire. Eighty-eight percent of the participants had heard of rabies but only 39% of the participants who had heard of rabies had adequate knowledge about rabies. Multivariable logistic regression analysis showed that residing in the south [OR = 9.25 (95% CI: 6.01-14.53)] and having seen a rabies case [OR = 2.46 (95% CI: 1.6-3.82)] were significantly associated with having adequate knowledge about rabies. Based on our scoring criteria, 65% of the total participants who had heard of rabies had a favorable attitude towards rabies control and prevention programs. The participants residing in the east were two times more likely to have a favourable attitude than their counterparts in the south [OR = 2.08 (95% CI: 1.43-3.05)]. More than 70% of the participants reported engaging in farm activities such as examining the oral cavity of sick cattle and assisting cattle during parturition. Only 25% of the participants reported using personal protective equipment while undertaking these activities. Despite a high level of rabies awareness, we observed that there is a lack of comprehensive knowledge about rabies regarding susceptible hosts, transmission routes, the health outcome of rabies infection in humans, and appropriate health-seeking behaviours. This study highlights the need to strengthen rabies education programs in rural communities to address the knowledge gaps that have been identified.

Beneficial Effect of Silymarin in Pressure Overload Induced Experimental Cardiac Hypertrophy.

The present investigation was undertaken to study the effect of silymarin on cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) in Wistar rats. Silymarin was administered for 9 weeks at the end of which we evaluated hypertrophic, hemodynamic, non-specific cardiac markers, oxidative stress parameters, and determined mitochondrial DNA concentration. Hypertrophic control animals exhibited cardiac hypertrophy, altered hemodynamics, oxidative stress, and decreased mitochondrial DNA (mtDNA) concentration. Treatment with silymarin prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress and increased mitochondrial DNA concentration. Docking studies revealed that silymarin produces maximum docking score with mitogen-activated protein kinases (MAPK) p38 as compared to other relevant proteins docked. Moreover, PAAC-control rats exhibited significantly increased expression of MAPK p38ß mRNA levels which were significantly decreased by the treatment of silymarin. Our data suggest that silymarin produces beneficial effects on cardiac hypertrophy which are likely to be mediated through inhibition of MAPK p38ß.

Lung disease associated with occupational styrene exposure.

Despite reports of pulmonary toxicity due to styrene, guidelines on acceptable styrene exposure levels have been based on risk of cancer and central nervous system and liver toxicity and not on respiratory effects. Many reports have linked exposure to styrene vapor in occupational settings to various forms of non-malignant pulmonary disorders including bronchiolitis, hypersensitivity pneumonitis, and occupational asthma. We report two cases in which the same tasks performed in a single workplace resulted in exposure to styrene vapor with subsequent development of acute respiratory symptoms associated with impaired gas exchange and imaging and histopathologic findings consistent with bronchiolitis and organizing pneumonia. Both patients gradually recovered once their workplace exposure to styrene was terminated. Clinicians, employers, and insurers should be aware of the potential for pulmonary toxicity from exposure to styrene.

Revisiting an old disease? Risk factors for bovine enzootic haematuria in the Kingdom of Bhutan.

Bovine enzootic haematuria (BEH) is a debilitating disease of cattle caused by chronic ingestion of bracken fern. Control of BEH is difficult when bracken fern is abundant and fodder resources are limited. To fill a significant knowledge gap on modifiable risk factors for BEH, we conducted a case-control study to identify cattle management practices associated with BEH in the Bhutanese cattle population. A case-control study involving 16 of the 20 districts of Bhutan was carried out between March 2012 and June 2014. In Bhutan sodium acid phosphate and hexamine (SAP&H) is used to treat BEH-affected cattle. All cattle greater than three years of age and treated with SAP&H in 2011 were identified from treatment records held by animal health offices. Households with at least one SAP&H-treated cattle were defined as probable cases. Probable case households were visited and re-classified as confirmed case households if the BEH status of cattle was confirmed following clinical examination and urinalysis. Two control households were selected from the same village as the case household. Households were eligible to be controls if: (1) householders reported that none of their cattle had shown red urine during the previous five years, and (2) haematuria was absent in a randomly selected animal from the herd following clinical examination. Details of cattle management practices were elicited from case and control householders using a questionnaire. A conditional logistic regression model was used to quantify the association between exposures of interest and household BEH status. A total of 183 cases and 345 controls were eligible for analysis. After adjusting for known confounders, the odds of free-grazing for two and three months in the spring were 3.81 (95% CI 1.27-11.7) and 2.28 (95% CI 1.15-4.53) times greater, respectively, in case households compared to controls. The odds of using fresh fern and dry fern as bedding in the warmer months were 2.05 (95% CI 1.03-4.10) and 2.08 (95% CI 0.88-4.90) times greater, respectively, in cases compared to controls. This study identified two husbandry practices that could be modified to reduce the risk of BEH in Bhutanese cattle. Avoiding the use of bracken fern as bedding is desirable, however, if fern is the only available material, it should be harvested during the colder months of the year. Improving access to alternative fodder crops will reduce the need for householders to rely on free-grazing as the main source of metabolisable energy for cattle during the spring.

A cross-sectional survey of population demographics, the prevalence of major disease conditions and reason-specific proportional mortality of domestic cattle in the Kingdom of Bhutan.

We describe the population demographics, rudimentary measures of reproductive performance, the prevalence of major disease conditions and reason-specific proportional mortality for cattle owned by villagers in 16 dzongkhags (districts) in Bhutan based on the findings of a cross-sectional study carried out between March 2012 and May 2014. The animal health issues that were of concern for livestock owners are also identified. Study households were selected using a stratified, two-stage cluster design. Districts (dzongkhags) formed the strata. Villages within dzongkhags were the first sampling stage and households within villages the second sampling stage. All cattle within each selected household comprised the study population. Questionnaires were collected from 409 households with 1480 standing cattle. A total of 71.0% (95% CI 67.9%-74.1%) of the standing cattle population were female and the median age of cattle was 5 years (Q25 3 years; Q75 7 years). Exotic breeds of cattle (Jerseys, Brown Swiss, and their crosses) comprised 41.4% of the cattle population with local breeds making up the remainder. Although exotic breeds of cattle had a significantly lower age at first calving (median 4 years) compared to local breeds (median 4.8 years) there was no significant difference in the number of calving events per cow for the two breed groups. Diarrhoea was the most prevalent disease condition with 2.8 (95% CI 1.5-4.6) cases per 100 animals followed by bovine enzootic haematuria with 1.9 (95% CI 1.0-3.3) cases per 100 animals. The most frequently cited cause of death was misadventure (proportional mortality 26.2%, 95% CI 15.7%-39.2%) followed by old age (17.8%, 95% CI 9.5%-29.4%). A lack of access to adequate fodder and pasture was the animal health issue that was cited by interviewees most frequently. We provide no evidence that exotic breeds of cattle have superior reproductive performance compared with local breeds. The major cattle health concern cited by interviewees, lack of access to fodder, is likely to contribute to suboptimal productivity and the relatively high incidence of bovine enzootic haematuria in this population. We propose that a prospective cohort study of Bhutanese cattle is warranted to more fully elucidate factors affecting the productivity and longevity of cattle in Bhutan.

Reemergence of rabies in Chhukha district, Bhutan, 2008.

From January through July 2008, rabies reemerged in the Chhukha district of southwestern Bhutan. To clarify the distribution and direction of spread of this outbreak, we mapped reported cases and conducted directional tests (mean center and standard deviational ellipse). The outbreak resulted in the death of 97 animals (42 cattle, 52 dogs, and 3 horses). Antirabies vaccine was given free of charge to ≈674 persons suspected to have been exposed. The outbreak spread south to north and appeared to follow road networks, towns, and areas of high human density associated with a large, free-roaming, dog population. The outbreak was controlled by culling free-roaming dogs. To prevent spread into the interior of Bhutan, a well-coordinated national rabies control program should be implemented in disease-endemic areas.

Immunogenicity of therapeutic proteins. Part 1: impact of product handling.

The patents of first-generation biopharmaceutical proteins are expiring, creating opportunities for biosimilar products. Unlike conventional generic pharmaceuticals, the development of biosimilar products is far more complex and requires more than a simple demonstration of pharmacological bioequivalence to establish efficacy and safety. The main concern with biosimilar products, as for any therapeutic protein, is immunogenicity and with it the potential for serious clinical sequelae. In the absence of adequate predictors of immunogenicity outside the clinical trial setting, biosimilar products should be evaluated in the same way that any novel pharmaceutical is evaluated. Herein, the factors involved in breaking host tolerance following administration of a therapeutic protein are discussed. The impact of product handling on immunogenicity is considered in the context of some hard-fought lessons that have helped to shape the current era of biopharmaceutical manufacturing, packaging, distribution, storage, and quality assurance.

Immunogenicity of therapeutic proteins. Part 3: impact of manufacturing changes.

Immunogenicity of biopharmaceuticals relates to the intrinsic complexity of proteins as well as the complexities of the manufacturing process. The manufacture of biopharmaceuticals involves a number of complex processing steps designed to create a highly pure, stable, safe, and effective product. The process often lasts many months and can be divided into seven stages - host cell development, master cell bank establishment, protein production, purification, analysis, formulation, and storage and handling. Even minor variations at any of these stages can lead to clinically relevant changes in efficacy and/or safety of the end product. Due to the complexity of the process and the inherently unstable nature of proteins outside the body, compositional changes can occur, leading to decreased biological activity, alteration of molecular structure, and possible increased risk of host immune responses following administration. Examples are discussed whereby immunogenicity associated with some of these changes has occurred with potentially serious clinical consequences.

Immunogenicity of therapeutic proteins. Part 2: impact of container closures.

Immunogenicity as a potential consequence of therapeutic protein administration is increasingly being scrutinized in the biopharmaceuticals industry, particularly with the imminent introduction of biosimilar products. Immunogenicity is an important safety aspect requiring rigorous investigation to fully appreciate its impact. Factors involved in product handling, such as storage temperature, light exposure, and shaking, have been implicated in immunogenicity, while container closure systems are no less important. Intended to provide a stable environment for the dosage form, container closures may also interact with a product, affecting performance and potentially enhancing immunogenicity. Glass surfaces, air-liquid interfaces, and lubricants can mediate protein denaturation, while phthalates in plastics and latex rubber are sources of extractables and leachates that may contaminate a product, causing allergic reactions and increasing immunogenicity. The manufacture of therapeutic proteins therefore requires rigorous safety evaluations not just in the context of the product, but also product containment.

Development of a sensitive size exclusion HPLC method with fluorescence detection for the quantitation of recombinant human erythropoietin (r-HuEPO) aggregates.

Human erythropoietin produced by recombinant DNA technology, is now marketed worldwide for the treatment of anemias associated with chronic renal failure and chemotherapy. No sensitive methods, which can determine r-HuEPO dimer or oligomer aggregate content in formulated products, have been published to date. This report describes the development and validation of a sensitive size exclusion high performance liquid chromatography (HPLC) method for the quantitation of r-HuEPO aggregates in formulations containing 0.03% polysorbate 80. A Waters Alliance 2690 HPLC system connected to a TosoHaas TSKgel G3000 SWxl (7.8 mm x 30 cm, 250 A pore size, 5 microm particle size) column and a Waters 474 fluorescence detector was used. The mobile phase for the SEC-HPLC method consists of isopropyl alcohol-potassium phosphate (0.1 M)/potassium chloride buffer (pH 6.8+/-0.1, 0.2 M) (25:75, v/v). The flow rate was 0.3 mL/min and the method run time was 60 min. The SEC-HPLC method presented here was shown to be specific for r-HuEPO total aggregates (dimer and oligomers) and allows for their quantitation at 80 ng/mL or 4 ngs/injection, in the presence of r-HuEPO monomer and the pharmaceutical excipients, glycine (5 mg/mL), sodium chloride (4.3 mg/mL), and 0.03% polysorbate 80. The finalized method is stability-indicating and is suitable for determining r-HuEPO aggregates between 0.2 and 0.5% levels in the formulated product of r-HuEPO. This method offers a robust way to measure total aggregates on a routine basis with a high sensitivity for use in product quality control.

A modified posterior approach for upper eyelid retraction.

PURPOSE: To describe and review a graded technique for lowering the upper eyelid from a posterior approach, recessing or resecting Müller muscle and levator aponeurosis but leaving a central pillar of Müller muscle intact, occasionally including a temporal tarsorrhaphy or superior tarsal strip where needed, and performing tissue dissection with a hot-wire cautery instrument. METHODS: A 10-year retrospective chart review was performed. Where follow-up was less than 6 months, telephone interviews were conducted to assess patient satisfaction with the procedure. Statistical analysis was performed using an unpaired t test. RESULTS: Ninety-nine patients (161 eyelids, 62 bilateral and 37 unilateral) with a mean age of 47 years (range, 21-82 years) were studied. The mean follow-up period was 61 months. The mean preoperative and postoperative margin reflex distances (MRD1) were 7.3 mm (range, 4.5-10 mm) and 4.3 mm (range, 2-7 mm), respectively. Eighty-nine percent (144/161 eyelids) achieved the target result of an MRD1 of 4 +/- 1 mm after one procedure. Fifteen eyelids (9% of operated eyelids) required a second procedure, and in this group, 2 (13% of the reoperated eyelids) underwent a third procedure. Although bilateral cases were more likely to achieve symmetry (p = 0.0071), 90% of either unilateral or bilateral cases achieved a postoperative MRD1 of 4 +/- 1 mm. Both mild (MRD1 of 5-7 mm) and severe (MRD1 > 7 mm) cases of eyelid retraction achieved similar operative outcomes. In the first 6 months after surgery, complications included undercorrection (8 eyelids), overcorrection (2 eyelids), and pyogenic granuloma (2 eyelids). None had a flattened upper eyelid contour. Late recurrence of retraction was seen in 9 eyelids. Mean operative time was 16 minutes per eyelid. CONCLUSIONS: This technique of lowering the retracted upper eyelid is effective even in severe cases of eyelid retraction. Minimal complications were encountered, and upper eyelid contours were well preserved. The use of hot-wire cautery dissection proved useful in shortening operative time.

An in vivo model to assess factors that may stimulate the generation of an immune reaction to erythropoietin.

The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (s.c.) administration of epoetin alfa (EPREX) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, in vivo models were developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). It was difficult to generate anti-EPO antibodies in mice. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to increase both the frequency of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some mice exhibited a reduction in hematocrit, suggesting neutralization of endogenous EPO by anti-EPO antibodies. To evaluate the primary lead identified in the technical investigation, leachates from the uncoated syringe stoppers of EPREX syringes, a surrogate antigen (chicken egg albumin, OVA) was used to avoid possible interferences that could arise from the use of an endogenous protein like EPO. These leachates yielded a positive, concentration-dependent antibody response in the OVA animal model, demonstrating their adjuvant properties and providing support for the hypothesis generated through the technical investigation that leachates were capable of enhancing the immune response to rHuEPO.