Comparison of Baseline Characteristics, Sociodemographics, and Gynecological Risk Factors Associated with Secondary Infertility of Females in Pakistan.

Introduction: Secondary infertility is characterized by the inability to conceive for a period of 1 year, after having previously conceived at least once. Objectives: To explore the risk factors of secondary infertility and compare sociodemographics and anthropometric variables of each studied group. Methods: Study was conducted at University Institute of Public Health, Faculty of Allied Health Sciences, The University of Lahore, collecting data from Gilani Ultrasound Center in 18 months after approval of synopsis. Total 690 females (345 cases and 345 controls) were enrolled. Participants were included in case group if they were 20-45 years of age, having any parity, and confirmed diagnosis of secondary infertility. Results: The mean age of cases and controls was 33.08 ± 4.17 years and 31.37 ± 4.36 years, respectively. The mean body mass index (BMI) in cases was 27.61 ± 4.27 kg/m2, and in controls the mean BMI was 25.52 ± 4.30 kg/m2. There was not a significant difference among religion that shows no association (p = 0.73) with secondary infertility as profession has association with it (p = 0.01). History of polycystic ovary syndrome, pelvic inflammatory disease, endometriosis, uterine fibroids, menorrhagia, intermenstrual bleeding, and history of abortion are associated with secondary infertility. Conclusions: While several sociodemographic features and medical disorders have been associated to secondary infertility, it is vital to stress that not all of these factors are controllable by medical therapy. Factors like age and certain medical issues may be unaffected by intervention. However, for controllable variables like BMI and certain medical diseases, focused therapies and lifestyle changes may reduce the chance of subsequent infertility.

Blue carbon assessments of seagrass and mangrove ecosystems in South and Southeast Asia: Current progress and knowledge gaps.

Coastal blue carbon ecosystems can be an important nature-based solution for mitigating climate change, when emphasis is given to their protection, management, and restoration. Globally, there has been a rapid increase in blue carbon research in the last few decades, with substantial investments on national scales by the European Union, the USA, Australia, Seychelles, and Belize. Blue carbon ecosystems in South and Southeast Asia are globally diverse, highly productive and could represent a global hotspot for carbon sequestration and storage. To guide future efforts, we conducted a systematic review of the available literature on two primary blue carbon ecosystems-seagrasses and mangroves-across 13 countries in South and Southeast Asia to assess existing national inventories, review current research trends and methodologies, and identify existing knowledge gaps. Information related to various aspects of seagrass and mangrove ecosystems was extracted from 432 research articles from 1967 to 2022. We find that: (1) blue carbon estimates in several countries have limited data, especially for seagrass meadows compared to mangrove ecosystems, although the highest reported carbon stocks were in Indonesia and the Philippines with 4,515 and 707 Tg within mangrove forest and 60.9 and 63.3 Tg within seagrass meadows, respectively; (2) there is a high difference in the quantity and quality of data between mangrove and seagrass ecosystems, and the methodologies used for blue carbon estimates are highly variable across countries; and (3) most studies on blue carbon stocks are spatially biased towards more familiar study areas of individual countries, than several lesser-known suspected blue carbon hotspots. In sum, our review demonstrates the paucity and variability in current research in the region, and highlights research frontiers that should be addressed by future research before the robust implementation of these ecosystems into national climate strategies.

Novel mutations in genes of the IL-12/IFN-γ axis cause susceptibility to tuberculosis.

BACKGROUND: The IL-12/23/ISG15-IFN-γ pathway is the main immunological pathway for controlling intra-macrophagic microorganisms such as Mycobacteria, Salmonella, and Leishmania spp. Consequently, upon mutations in genes of the IL-12/23/ISG15-IFN-γ pathway cause increased susceptibility to intra-macrophagic pathogens, particularly to Mycobacteria. Therefore, the purpose of this study was to characterize the mutations in genes of the IL-12/23/ISG15-IFN-γ pathway in severe tuberculosis (TB) patients. METHODS: Clinically suspected TB was initially confirmed in four patients (P) (P1, P2, P3, and P4) using the GeneXpert MTB/RIF and culturing techniques. The patients' Peripheral blood mononuclear cells (PBMCs) were then subjected to ELISA to measure Interleukin 12 (IL-12) and interferon gamma (IFN-γ). Flow cytometry was used to detect the surface expressions of IFN-γR1 and IFN-γR2 as well as IL-12Rß1and IL-12Rß2 on monocytes and T lymphocytes, respectively.The phosphorylation of signal transducer and activator of transcription 1(STAT1) on monocytes and STAT4 on T lymphocytes were also detected by flow cytometry. Sanger sequencing was used to identify mutations in the IL-12Rß1, STAT1, NEMO, and CYBB genes. RESULTS: P1's PBMCs exhibited reduced IFN-γ production, while P2's and P3's PBMCs exhibited impaired IL-12 induction. Low IL-12Rß1 surface expression and reduced STAT4 phosphorylation were demonstrated by P1's T lymphocytes, while impaired STAT1 phosphorylation was detected in P2's monocytes. The impaired IκB-α degradation and abolished H2O2 production in monocytes and neutrophils of P3 and P4 were observed, respectively. Sanger sequencing revealed novel nonsense homozygous mutation: c.191 G>A/p.W64 * in exon 3 of the IL-12Rß1 gene in P1, novel missense homozygous mutation: c.107 A>T/p.Q36L in exon 3 of the STAT1 gene in P2, missense hemizygous mutation:: c.950 A>C/p.Q317P in exon 8 of the NEMO gene in P3, and nonsense hemizygous mutation: c.868 C>T/p.R290X in exon 8 of CYBB gene in P4. CONCLUSION: Our findings broaden the clinical and genetic spectra associated with IL-12/23/ISG15-IFN-γ axis anomalies. Additionally, our data suggest that TB patients in Pakistan should be investigated for potential genetic defects due to high prevalence of parental consanguinity and increased incidence of TB in the country.

Seagrass ecosystem adjacent to mangroves store higher amount of organic carbon of Andaman and Nicobar Islands, Andaman Sea.

This study quantified the organic carbon (Corg) stocks in Thalassia hemprichii meadows that are (i) adjacent to mangroves (MG), and (ii) without mangroves (WMG), in tropical Andaman and Nicobar Islands (ANI) of India. In the top 10 cm of the sediment, Corg content was 1.8-fold higher at the MG sites than the WMG sites. The total Corg stocks (sediment + biomass) in the 144 ha of seagrass meadows at MG sites (988.74 ± 138.77 Mg C) was 1.9-fold higher than in 148 ha of WMG sites. Protection and management of T. hemprichii meadows of ANI can lead to emission avoidance of around 5447.33 (MG; 3595.12 + WMG: 1852.21) tons of CO2. The social cost of the carbon stocks in these T. hemprichii meadows is around US$ 0.30 and 0.16 million at the MG and WMG sites, respectively, showcasing the importance of ANI's seagrass ecosystems as nature-based solutions for climate change mitigation.

Predicted risk factors associated with secondary infertility in women: univariate and multivariate logistic regression analyses.

Introduction: Infertile women are those who regularly engage in unprotected intercourse for a period of at least 1 year and are unable to become clinically pregnant. Primary infertility means the inability of couples to conceive, without any previous successful pregnancies. Secondary Infertility refers to the inability to get pregnant for 12 months, after having a previous pregnancy for one time at least. The objectives of the current study were to analyze risk factors for secondary infertility and compare the predictive accuracy of artificial neural network (ANN) and multiple logistic regression models. Methods: The study was conducted at The University Institute of Public Health collecting data from Gilani Ultrasound Center 18 months after approval of synopsis. A total of 690 women (345 cases and 345 controls) were selected. The women selected for the case group had to be 20-45 years of age, had any parity, and had a confirmed diagnosis of secondary infertility. Results: Multiple logistic regression (MLR) and ANN were used. The chance of secondary infertility was 2.91 times higher in women living in a joint family [odds ratio (OR) = 2.91; 95% confidence interval (CI) (1.91, 4.44)] and was also 2.35 times higher for those women who had relationship difficulties with their husband [OR = 2.35; 95% CI (1.18, 4.70)]. Marriage at an earlier age was associated with secondary infertility with ß being negative and OR being < 1 [OR = 0.94; 95% CI (0.88, 0.99)]. For the logistic regression model, the area under the receiver operative characteristic curve (ROC) was 0.852 and the artificial neural network was 0.87, which was better than logistic regression. Discussion: Identified risk factors of secondary infertility are mostly modifiable and can be prevented by managing these risk factors.

Lack of ecological data hinders management of ecologically important saltmarsh ecosystems: A case study of saltmarsh plant Porterasia coarctata (Roxb.).

Saltmarsh ecosystems though ecologically important are one of the least studied ecosystems in Asia. This study reviewed the published literature from 1988 to 2021 of India to assess the current status of the data deficient saltmarsh species Porterasia coarctata (Roxb.) within its distribution limits. This saltmarsh species inhabits the lower intertidal silty-sandy habitats of India's west coast and silty-clay habitats of the east coast. In the lower intertidal zone, P. coarctata is mostly associated with Myrostachia wightiana, whereas in the upper intertidal zone the highest chance of presence was for Suaeda maritima (18%) and the lowest for Cressa cretica (1%), S. fruticosa (1%) and Scirpus littoralis (1%). The deep root system of P. coarctata helps in sediment accretion and facilitates the formation of mangrove ecosystems. From this study it was evident that most of the research on P. coarctata in India was part of survey of mangrove ecosystems. In India, significant knowledge gap exists on the reproductive ecology and population trends of this species. Most importantly, the genes responsible for salinity and submergence tolerance of P. coarctata are well documented, that can provide solutions for salt and submergence tolerant rice plants in coastal areas prone to sea level rise. The blue carbon storage potential of P. coarctata is higher than other saltmarsh plants, that can be leveraged as a nature-based solution for CO2 emission reductions. The ecosystem services of P. coarctata can also contribute towards achieving various sustainable development goals (SDG-1,2,6,13 and14). Coastal development, mangrove restoration and marine food provisioning are the most important drivers causing the decline of P. coarctata ecosystems across India. This study proposes a long-term coastal monitoring plan for essential conservation and management of existing P. coarctata beds and preventing further degradation and loss of these ecosystems. This study also showcases species-specific valuation of individual saltmarsh plants at regional scale are essential to catalogue the most efficient saltmarsh plants that can play an important role in future climate change scenarios and serve as a global model.

In-Plane Seismic Strengthening of Brick Masonry Using Steel and Plastic Meshes.

Unreinforced masonry structures are vulnerable to seismic loading due to their brittle behavior, and must therefore be strengthened. This paper presents the seismic performance of brick masonry strengthened with steel and plastic meshes. For this purpose, twenty masonry wallets of (600 × 600 × 113 mm) were constructed, keeping the same materials and workmanship. Fifteen of them were reinforced using steel and plastic meshes. These specimens were tested for in-plane static cyclic diagonal tension (shear) behavior. The critical parameters, such as shear stress, strain, failure modes, ductility, energy dissipation, and stiffness degradation were investigated. Compared to reference and plastic-reinforced specimens, the steel-reinforced samples were found to be highly effective. Furthermore, the recommended category of steel increased the shear capacity, energy dissipation, and ductility ratio by 1.3, 14, and 6.3 times, respectively.

Assessing vaccine hesitancy among health-care workers in Jammu and Kashmir: A cross-sectional study.

BACKGROUND: The World Health Organization declared vaccine hesitancy as one of the planet's top 10 global health threats in 2019. With the rollout of the coronavirus disease-19 (COVID-19) vaccines, a survey was conducted to find out the hesitancy and the apprehensions that come along with taking COVID-19 vaccines among health-care workers (HCWs). MATERIALS AND METHODS: This was an online cross-sectional survey which was developed and shared through social media platforms among the HCWs of Kashmir. The survey captured demographic data and used a validated hesitancy measurement tool from January 2021 to February 2021. The data were analyzed by descriptive statistics and multivariable logistic regression using Stata 15 (Stata Corp. 2017. Stata Statistical Software: Release 15. College Station, TX: Stata Corp LLC). RESULTS: Willingness to take the COVID-19 vaccine when available was seen in 67.7% of the HCWs. Overall, 9.59% of respondents reported unwillingness to receive a vaccine for COVID-19, while 22.7% were unsure. The most commonly cited reason for willingness to get vaccinated was an understanding of the disease and vaccination, as reported by 81.5%. Being single was significantly related to an increased risk of vaccine hesitancy (adjusted odds ratio = 5.27, 95% confidence interval: 2.07-13.40). Among vaccine attitudes, concerns about the safety of the vaccine, unforeseen problems in children, and possible unknown future adverse effects of the vaccine were the most important determinants of unwillingness. CONCLUSIONS: A significant proportion of the HCWs showed vaccine hesitancy to the COVID-19 vaccine. Hesitancy attitudes were almost always driven by concern around the vaccine safety. States and health-care authorities need to recognize the massive trust deficit around the Covid-19 vaccine and use the popular media used by people to share credible and reliable information.

Vaccine hesitancy and coronavirus disease-19: Where do we stand?

BACKGROUND: Vaccine hesitancy is seen, globally, as a major factor that will determine future coronavirus disease-19 (COVID-19) spread and its effective management. This study aimed to identify COVID-19 vaccine perception, acceptance, confidence, hesitancy, and barriers among the general population. MATERIALS AND METHODS: This was an online survey which was developed and shared through social media platforms among the general population of Kashmir. The survey captured demographic data and used a validated hesitancy measurement tool. We analyzed the data using descriptive statistics and multivariable logistic regression using Stata 15 (Stata Corp. 2017. Stata Statistical Software: Release 15. College Station, TX, USA: Stata Corp LLC). RESULTS: A total of 835 responses were received. Most participants were males, with females compromising of 19.5% participants. 65.1% of participants were in the age group of 30-50, whereas 19.2% were below 30 years of age. 52.70% of respondents were willing to take the vaccine when available, while 32.5% of respondents were unsure about their decision of inoculation. The most cited reason for willingness to get vaccinated was an understanding of the disease and vaccination. 41.70% felt that the vaccines developed against COVID-19 have not been fully tested; therefore, concerns around the safety and its longer-term side effects were the reasons cited. Public health messaging should be tailored to address these concerns. CONCLUSIONS: Vaccine hesitancy is a global threat undermining the control of preventable infections. The government should take proactive steps to address the factors that may potentially impact the benefits expected from the introduction of a COVID-19 vaccine in the union territory.

Trace metal accumulation in seagrass and saltmarsh ecosystems of India: comparative assessment and bioindicator potential.

Coastal macrophytes serve as bioindicators of coastal trace metal contamination. In this study, trace metal levels in India's seagrass and saltmarsh ecosystems were assessed for their suitability as bioindicators of metal contamination. Trace metal accumulation and bioindicator potential of both seagrasses and saltmarshes were found to be metal and species-specific. Higher concentrations of Cu, Fe, Mg and Mn were found in the tissues of seagrasses, while saltmarshes showed higher accumulation of Cd, Cr, Hg, Ni, Pb and Zn. The leaves of seagrasses are suitable bioindicator of metals in the water column, while the roots and rhizomes of saltmarshes/seagrasses are suitable bioindicators of metals in the sediment. This study proposes the development of a monitoring network using seagrasses and saltmarss as model organisms for short and long-term monitoring of coastal metal contamination. Determining the phytotoxic levels of trace metals in seagrasses and saltmarsh is important for monitoring plant die-offs and loss.

Role of High Resolution Computed Tomography chest in the diagnosis and evaluation of COVID -19 patients -A systematic review and meta-analysis.

BACKGROUND: Recent studies reported that CT scan findings could be implicated in the diagnosis and evaluation of COVID-19 patients. OBJECTIVE: To identify the role of High-Resolution Computed Tomography chest and summarize characteristics of chest CT imaging for the diagnosis and evaluation of SARS-CoV-2 patients. METHODOLOGY: Google Scholar, PubMed, Science Direct, Research Gate and Medscape were searched up to 31 January 2020 to find relevant articles which highlighted the importance of thoracic computed tomography in the diagnosis as well as the assessment of SARS-CoV-2 infected patients. HRCT abnormalities of SARS-CoV-2 patients were extracted from the eligible studies for meta-analysis. RESULTS: In this review, 28 studies (total 2655 patients) were included. Classical findings were Ground Glass Opacities (GGO) (71.64 %), GGO with consolidation (35.22 %), vascular enlargement (65.41 %), subpleural bands (52.54 %), interlobular septal thickening (43.28 %), pleural thickening (38.25 %), and air bronchograms sign (35.15 %). The common anatomic distribution of infection was bilateral lung infection (71.55 %), peripheral distribution (54.63 %) and multiple lesions (74.67 %). The incidences were higher in in the left lower lobe (75.68 %) and right lower lobe (73.32 %). A significant percentage of patients had over 2 lobes involvement (68.66 %). CONCLUSION: Chest CT-scan is a helpful modality in the early detection of COVID-19 pneumonia. The GGO in the peripheral areas of lungs with multiple lesions is the characteristic pattern of COVID-19. The correct interpretation of HRCT features makes it easier to detect COVID-19 even in the early phases and the disease progression can also be accessed with the help of the follow-up chest scans.

Clinico-radiological profile of COVID-19 in Kashmiri population: A descriptive study.

AIM: The purpose of our study was to assess the presentation of COVID-19 disease in terms of clinical and radiological features in our population. METHODS: 64 RT-PCR documented COVID-19 patients were included in the study. Clinical, biochemical, and radiological data were collected and analyzed retrospectively from last week of March to 30th April 2020. RESULTS: Out of the 64 patients, 38 (59.4%) were males, 44 (68.7%) had a history of contact with COVID-19 positive patient. 26.6%patients were in the age group of 21-30 years. 53.1% patients were asymptomatic while as cough and fever were the most common symptoms in 21.8 and 20.3% patients, respectively. Anosmia was present in four patients. Hypertension and hypothyroidism were the most common comorbid illnesses among the study population in 9.4% patients each. Lymphopenia was present in 38% of patients CRP was increased in 83% patients, LDH in 90.2%, and ferritin in 51.5% of patients. 17 (26.6%) patients had bilateral disease in CT. RUL was the most common lobe involved in 18 (28.1%) patients. GGO and consolidation were seen in 22 (34.45) and 13 (20.3%) patients, respectively. Vessel enlargement was observed in 11 (17.2%) patients. All five lobes were involved in 9 (14.1%) patients. Five patients developed severe disease with respiratory comprise; two of them eventually died. CONCLUSION: The clinical and radiological characteristics of COVID-19 patients vary among different populations. Although there are no radiological features which seems to be characteristic of COVID-19, but CT helps in evaluation of the patients as many asymptomatic ones have some radiological findings suggestive of viral pneumonia.

The flavonoid 6-hydroxyflavone prevention of cisplatin-induced nephrotoxicity.

In this study, the flavonoid, 6-hydroxyflavone was investigated for its renal protective activity in the cisplatin rat model of nephrotoxicity. Male Sprague-Dawley rats weighing 200-250 g were included in the study. 6-Hydroxyflavone was daily administered at 25 and 50 mg/kg (i.p.), while ascorbic acid was used as a positive control and injected (i.p.) at 50 mg/kg for 15 days. The nephrotoxicity was evoked with a single cisplatin injection at 7.5 mg/kg on the tenth day of treatment. The renal function and levels of oxidative stress markers were assessed. Each tissue slide of different groups was observed under a compound microscope attached with a digital camera. Cisplatin significantly decreased the overall body weight with an increase in serum creatinine and urea and production of severe histopathological and oxidative stress in the kidneys. The daily treatment with 6-hydroxyflavone significantly attenuated the cisplatin associated detrimental changes in the body weight, and serum levels of creatinine and urea at both 25 mg/kg (P<0.05) and 50 mg/kg (P<0.01). The 6-hydroxyflavone treatment also preserved the renal histoarchitecture from the toxicological influence of cisplatin as evident from a significant reduction in the severity of histopathological changes in the renal tissues. Moreover, 6-hydroxyflavone also reduced the cisplatin-induced lipid peroxidation and corrected the renal antioxidant status. A similar protective effect was observed with the positive control, ascorbic acid (50 mg/kg). These findings show that the flavonoid 6-hydroxyflavone has potential nephroprotective properties and can be used for the management of chemotherapy associated renal disturbances.

ACE2 and SARS-CoV-2 Expression in the Normal and COVID-19 Pancreas

Diabetes is associated with increased mortality from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of the key molecule for SARS-CoV-2 infection of cells, angiotensin-converting enzyme-2 (ACE2). Specifically, we analyzed five public scRNAseq pancreas datasets and performed fluorescence in situ hybridization, Western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) patients. These in silico and ex vivo analyses demonstrated pancreatic expression of ACE2 is prominent in pancreatic ductal epithelium and the microvasculature, with rare endocrine cell expression of this molecule. Pancreata from COVID-19 patients demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression primarily limited to ducts. SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, appears an unlikely central pathogenic feature of COVID-19 as it relates to diabetes.

Effect of Coconut Fiber Length and Content on Properties of High Strength Concrete.

Recently, the addition of natural fibers to high strength concrete (HSC) has been of great interest in the field of construction materials. Compared to artificial fibers, natural fibers are cheap and locally available. Among all natural fibers, coconut fibers have the greatest known toughness. In this work, the mechanical properties of coconut fiber reinforced high strength concrete (CFR-HSC) are explored. Silica fume (10% by mass) and super plasticizer (1% by mass) are also added to the CFR-HSC. The influence of 25 mm-, 50 mm-, and 75 mm-long coconut fibers and 0.5%, 1%, 1.5%, and 2% contents by mass is investigated. The microstructure of CFR-HSC is studied using scanning electron microscopy (SEM). The experimental results revealed that CFR-HSC has improved compressive, splitting-tensile, and flexural strengths, and energy absorption and toughness indices compared to HSC. The overall best results are obtained for the CFR-HSC having 50 mm long coconut fibers with 1.5% content by cement mass.

Application of tuned liquid column ball damper (TLCBD) for improved vibration control performance of multi-storey structure.

Tuned liquid column ball damper (TLCBD) is a passive control device used for controlling the building vibrations induced from wind or earthquakes. TLCBD is a modified form of conventional tuned liquid column damper (TLCD). This paper studies the effect of TLCBD on the four-storey steel frame structure. The performance of the TLCBD is also compared with conventional TLCD. The analytical model of both TLCD and TLCBD is presented here. The effectiveness of these analytical models is examined experimentally by series of shaking table tests under different excitation levels including harmonic loadings and seismic excitations. In TLCBD, the vibration is reduced significantly as compared to TLCD by using steel ball as a moving orifice. The difference in diameter of steel ball and tube, containing the liquid column, acts as an orifice which moves with the movement of the ball. This moving orifice phenomenon enhanced the vibration reduction effect by resisting the water motion in the TLCBD. Root mean square (RMS) and peak values of acceleration were calculated for each loading and each storey of uncontrolled and controlled structures. Comparison of the time histories of controlled and uncontrolled structures for different loadings is also reported. Results indicate that the TLCBD is more effective in the earthquake scenarios as compared to the harmonic excitations. The TLCBD controls the vibration of the primary structure significantly in vibration reduction.

Progressive structural capacity loss assessment-A framework for modern reinforced concrete buildings.

By the virtue of burgeoning terrorism, the exponential growth of advanced weaponry, and allied aids for explosions, it is quite evident that infrastructural facilities in the world have increasingly become more susceptible to sabotaging activities. The ever enhancing employment of reinforced concrete (RC) in the construction industry around the globe, the progressive collapse mechanisms, and respective mitigation strategies in the context of terrorism have garnered quite an attraction by the structural engineering community. The proficiency to envisage the complete collapse under the chain reaction of structural failures, partial collapse of key structural members, or the strength degradation of fundamental structural elements under the blast or impact loading can deliver significant information to cope with partial or complete structural failure. It is quite convenient to say that during the service life, a structure may experience extreme loading conditions. The current study has proposed a new methodology to cover the effect of uncertainty involved in loading on key structural elements of new and complex structures by emphasizing a very realistic structural capacity loss mechanism that allows the incremental reduction in the structural capacities of pivotal structural elements against any sort of impact loading instead of their complete annihilation. To demonstrate the application of the proposed methodology, a 13-story complex structure was selected that was comprised of a diverse structural configuration. The outcomes and results ensured the structural integrity against the applied loadings, as well as the effectiveness of the proposed methodology.

SERPINA1 Hepatocyte-Specific Promoter Polymorphism Associate with Chronic Obstructive Pulmonary Disease in a Study of Kashmiri Ancestry Individuals.

PURPOSE: Different mutations in coding and non-coding sequences of the SERPINA1 gene have been implicated in the pathogenesis of COPD. However, - 10T/C mutation in the hepatocyte-directed promoter region has not been associated with COPD pathogenesis so far. Here, we report an increased frequency of - 10C genotype that is associated with decreased levels of serum alpha1-antitrypsin (α1AT) in COPD patients. METHODS: The quantification of serum α1AT was done by ELISA, the phenol-chloroform method was used for DNA extraction, PCR products were directly sequenced. The IBM SPSS Statistics v21 software was used for statistical analyses of the data. RESULTS: The mean serum α1AT level was found to be 1.203+0.239 and 3.162+0.160 g/L in COPD cases and in control, respectively. The - 10C allele is associated with an increased risk of COPD [OR, 3.50 (95%CI, 1.86-6.58); p < 0.001]. The combined variant genotype (TT+CC) was significantly found associated with an increased risk of COPD [OR, 3.20 (95% CI, 1.47-6.96); p = 0.003]. A significant association of the family history with COPD (overall p value= 0.0331) suggests that genetics may play an important role in the pathogenesis of COPD. CONCLUSION: The polymorphism associated with hepatocyte-specific promoter region (- 10T/C) is likely to be associated with the pathogenesis of COPD. It is quite possible that the change of the base in the hepatocyte-specific promoter of the SERPINA1 gene can modulate its strength, thereby driving the reduced expression of α1AT.

Peginterferon beta-1a versus other self-injectable disease-modifying therapies in the treatment of relapsing-remitting multiple sclerosis in Scotland: a cost-effectiveness analysis.

AIMS: Peginterferon beta-1a 125 mcg administered subcutaneously every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved in January 2015 by the Scottish Medicines Consortium. This study assesses long-term clinical and economic outcomes of peginterferon beta-1a compared with other self-injectable DMTs (interferon beta-1a [22 mcg, 30 mcg, and 44 mcg], interferon beta-1b, and glatiramer acetate 20 mg) in the treatment of RRMS, from the National Health Service and Personal Social Services perspective in Scotland. METHODS: A previously published, validated Markov cohort model was adapted for this analysis. The model estimates changes in patient disability, occurrence of relapses, and other adverse events, and translates them into quality-adjusted life years and costs. Natural history data came from the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database, and a large population-based MS survey in the UK. The comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (2015 British Pounds) were obtained from public databases and literature. Clinical and economic outcomes were projected over 30 years and discounted at 3.5% per year. RESULTS: Over 30 years, peginterferon beta-1a was dominant compared with interferon beta-1a (22, 30, and 44 mcg), and interferon beta-1b, and cost-effective compared with glatiramer acetate 20 mg. Results were most sensitive to variations in each DMT's efficacy and acquisition costs. Deterministic and probabilistic sensitivity analyses confirmed the robustness of the results. LIMITATIONS: The impact of improved adherence with peginterferon beta-1a on clinical and economic outcomes and the impact of subsequent DMTs after treatment discontinuation were not considered. Oral and infused DMTs were not included as comparators. Conclusion Long-term treatment with peginterferon beta-1a improves clinical outcomes, while its cost profile makes it either dominant or cost-effective compared with other self-injectable DMTs for the treatment of RRMS in Scotland.

A novel missense mutation in the NADPH binding domain of CYBB abolishes the NADPH oxidase activity in a male patient with increased susceptibility to infections.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the five structural genes (CYBB, CYBA, NCF1, NCF2, and NCF4) that typically results in a decrease in function or inability to generate a respiratory burst, leading to defective killing of pathogens, including fungi and intracellular bacteria. Mutations in CYBB, encoding the gp91phox (also known as NOX2) result in X-linked CGD account for approximately 65% of CGD cases. Here, we aimed the characterization of a novel missense mutation c.1226C > A/p.A409E in the CYBB gene in a patient with X-linked CGD. Relevant clinical data of a male patient whose family was positive for XCGD was reviewed. Oxidative burst and NADPH protein expression was evaluated by flow cytometry, while Genetic analysis was performed by Sanger sequencing. Monocyte-derived macrophages (MDMs) were evaluated for their capacity for phagocytosis and growth suppression of the intracellular Mycobacterium tuberculosis (M. tuberculosis). We thus report the absence of an oxidative burst in the phagocytes of the patient. Flow cytometry evaluation revealed a normal expression of NADPH oxidase components in neutrophils and genetic analysis proved the existence of a novel missense c.1226C > A mutation in the CYBB gene resulting in p.A409E. Further, we have showed that the patient's MDMs were unhindered in their ability to take up mycobacteria normally. Instead, the MDMs failed to control the intracellular proliferation of M. tuberculosis, a phenotype that improved in the presence of recombinant human interferon-gamma (rhIFN-γ). This work expands the genetic spectrum of X-linked CGD and demonstrates improvement in macrophage function in X91+CGD patient by rhIFN-γ.