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This article focuses on the effect of parental migration on the care and educational performance of left-behind children of migrant families. This ethnographic study was conducted among the Kham people in Kankri, Rukum East district of the western mid-hill region of rural Nepal. Information was collected through participant observation, in-depth interviews, and living in the community in their setting. Income from parental labor migration provided families with food, clothing, access to basic health services, and investment in their children’s education. Left-behind children lacked parental care with proper guidance and emotional support, so they started taking alcohol, Charash (marijuana resin), and showing violent behavior. Children from migrant households have school absences and poorer educational performance as they are required to help with household work and lack guided learning at home. Children lose interest in studying, and those who miss upper-class admission because of seasonal migration drop out of school and join the migration. Parents select private or government schools for their children depending on remittance, quality of education, network availability, and future opportunities. Parents who had hardships during their migration are determined to educate their children in school, but they do not provide equal educational opportunities for boys and girls. Seasonal migrant workers anticipate that their children will engage in seasonal work during school breaks so that they can contribute to their schooling costs.

This article explores the socio-economic adjustment of rural migrants in the cities of Kathmandu Valley. This study was conducted among Sampang Rai migrants and utilizes the network theory of migration. Information was gathered through questionnaire using KoBoToolbox, in-depth interviews, and observation in the study areas. Sampang Rais migrate to the Kathmandu Valley to get an education, find better work, experience city life, help their families, get medical treatment, and learn new skills. The already established and available networks facilitate the selection of migration destinations and socio-economic adjustment in Kathmandu Valley. Friends, families, earlier migrants, and institutions assisted migrants to adjust socially and economically in the destination areas by providing information, physical resources, material resources, and sociocultural support. Sampang Rai migrants also made efforts to diversify their livelihood, keep strong connections with friends and families, join religious communities, learn new skills, exchange labour and encourage one another while they go through the process of socio-economic adjustment.

Nepali youths join foreign jobs with the dream of earning a lot of money and making a happy family. However, high visa fees and high costs of tickets impose a load of debt on the family. Nepal adopted the policy of free visas and free tickets to reduce the burden of debt. This article explains whether the dream of foreign labor migrants has come true after the government of Nepal adopted the policy of the 'free visa, free ticket' policy. The main objective of this article is to describe the experience of foreign labour migrants under the policy of the 'free visa, free ticket'. Seven years have passed since the 'free visa, free ticket' policy was introduced. Foreign labour migrant’s have-not been able to go abroad for work at zero migration cost yet. Due to ineffectiveness of this policy, people who go abroad have become a place to cheat on.

Motivation plays an important role in teaching learning activities. The motivational techniques make the classroom more interesting, effective, and successful as they help teachers teach the students effectively and students learn enthusiastically and interestingly. Considering the teaching learning activities using motivational techniques in the classroom, this paper explores the current practices of motivational strategies implemented by English teachers at the pre-primary level. A series of interviews with purposively selected pre-primary level English teachers and their class observations reveal various motivational strategies used in the teaching learning activities in the classrooms. The strategies the teachers used in their daily practices include greetings the students, playing with goods, using rhymes in the class, offering rewards, and calling lovely names to the students. The implication of the study is that the motivational strategies employed in the classroom activities are more effective, fruitful, and the students learn the teaching stuff in a joyful environment.

Nepal promulgated affirmative action or reservation policies for women, indigenous nationalities, and other groups to increase representation in the Civil Service. The reservation policy was made based on the assumption of Janajati (ethnic) as a unitary entity. Not all Janajati groups are the same economic, political, and social conditions. There are no government studies relating to under-representation and over-representation in Civil Service within Janajati groups. In this context, this paper provides answers to questions about which Janajati groups benefited more from the reservation policies in Civil Service. Is there a male creamy layer or a female creamy layer? Moreover, what is the situation of representation of Janajati based on the categorization of the Nepal government? This paper explores the representation of the Janajati in Civil Service after the implementation of the reservation policy. The paper argues that the provision of the reservation is more favorable for the advantaged Janajati group than the most marginalized Janajati group. Similarly, it is more favorable for male Janajati than female Janajati within the same group, thereby potentially reproducing social inequality within the Janjati in Nepal

Carbapenemases are the enzymes that catalyze β–lactam groups of antibiotics. The carbapenemase producers are resistant to β–lactam antibiotics and are usually multidrug-resistant bacteria challenging widely used therapeutics and treatment options. Therefore, the detection of carbapenemase activity among clinical isolates is of great therapeutic importance. We aimed to study the MDR and carbapenemase-producing Klebsiella pneumoniae and Pseudomonas aeruginosa isolated from various clinical samples at a tertiary care hospital in Nepal. A total of 3,579 clinical samples were collected from the patients visiting the Department of Microbiology, B&B Hospital, Gwarko, Lalitpur. The samples were processed to isolate K. pneumoniae and P. aeruginosa and then subjected to antibiotic susceptibility testing (AST) by the Kirby-Bauer disk diffusion method. Phenotypic detection of carbapenemase activity was performed in the imipenem-resistant isolates by the modified Hodge test (MHT). Of the total samples, 1,067 (29.8%) samples showed significant growth positivity, out of which 190 (17.3%) isolates were K. pneumoniae and 121 (11.3%) were P. aeruginosa. Multidrug resistance was seen in 70.5% of the K. pneumoniae isolates and 65.3% of the P. aeruginosa isolates. Carbapenemase production was confirmed in 11.9%, and 12.2% of the imipenem-resistant K. pneumoniae and P. aeruginosa isolates, respectively, by the MHT. This study determined the higher prevalence of MDR among K. pneumoniae and P. aeruginosa; however, carbapenemase production was relatively low.

Streptococcus suis serotype 2 (S. suis 2) is an important ubiquitous zoonotic pathogen. To date, regulatory factors and their implication in S. suis pathogenesis are not fully understood. Small non-coding RNAs (sRNAs) have been proven to function as important regulatory factors in bacterial pathogenesis and stress adaptation. Here, we identified a differentially downregulated S. suis 05ZYH33 sRNA after iron starvation by RNA-seq, which we named sRNA23. The presence of sRNA23 was further confirmed by RACE and Northern blot. Expression of sRNA23 was significantly altered under different environmental stresses such as nutritional starvation, osmotic pressure, oxidative stress, and lysozymal exposure. A sRNA23-deleted mutant exhibited relatively shorter streptococcal chains and weakened biofilm-forming ability. The mutation also resulted in decreased adherence of the S. suis 05ZYH33 to human laryngeal epidermoid carcinoma (HEp-2) cells, increased sensitivity to phagocytosis by RAW264.7 macrophages, and significantly reduced hemolytic activity. Furthermore, we observed that a sRNA23-deleted mutant had a low survival rate in pig whole blood and attenuated virulence in a mouse model. Moreover, based on RNA pull-down and electrophoretic mobility shift assay, we found that sRNA23 can directly bind to two proteins involved in adhesion and biofilm formation, namely, moonlighting protein FBA (fructose diphosphate aldolase) and rplB (50S ribosomal protein L2), respectively. Collectively, sRNA23 enhances S. suis 2 pathogenicity and the binding between sRNA23 and FBA/rplB might play an essential role in the adherence and biofilm-forming ability of S. suis 2. Abbreviation sRNA: small noncoding RNA; FBA: fructose diphosphate aldolase; rplB: 50S ribosomal protein L2; RACE: rapid amplification of cDNA ends; EMSA: electrophoretic mobility shift assay; THB: Todd-Hewitt broth; FBS: fetal bovine serum; BIP: 2,2ʹ-Bipyridine

The Mesoscale to Microscale Coupling team, part of the U.S. Department of Energy Atmosphere to electrons (A2e) initiative, has studied various important challenges related to coupling mesoscale models to microscale models for the use case of wind energy development and operation. Several coupling methods and techniques for generating turbulence at the microscale that is subgrid to the mesoscale have been evaluated for a variety of cases. Case studies included flat terrain, complex terrain, and offshore environments. Methods were developed to bridge the terra incognita, that scale from about 100 m through the depth of the boundary layer. The team used wind-relevant metrics and archived code, case information, and assessment tools and are making those widely available. Lessons learned and discerned best practices are described in the context of the cases studied for the purpose of enabling further deployment of wind energy.

This study analyzes the effect of migration on the left-behind family members in Nepal especially focusing on the family structure, livelihood, education, aging parents, reproductive health, and marital relationship. The review was done based on the published journal articles, dissertations, and organizational reports from 2015-2020 to explore the areas impacted by the migration. Seven thematic areas emerged and found both positive and adverse effects and association of migration on left behind family members of the migrants. The review also found the need for further research on the ways of communicating and supporting between migrants and left behind family members to reduce the adverse effect of the migration on the left behind members of the family. Furthermore, field studies can concentrate on ways to enable women to learn skills, techniques and technology to increase production and diversify livelihoods.

Here, we found that lncRNA-155KO mice lacking most of the lncRNA-155 sequences along with pre-miRNA-155, were more susceptible to influenza virus or pseudorabies virus infection than miRNA-155KO mice lacking only 19 bp of the miRNA-155 core sequence without affecting the expression of lncRNA-155, as evidenced by faster body weight loss, poorer survival, and higher viral load, suggesting an additional role of lncRNA-155 in regulating viral pathogenesis besides via processing miRNA-155. Congruously, miRNA-155-deleted lncRNA-155 significantly attenuated the viral infection.

STAT2 is an important transcription factor activated by interferons (IFNs) upon viral infection and plays a key role in antiviral responses. Interestingly, here we found that phosphorylation of STAT2 could be induced by several viruses at early infection stage, including influenza A virus (IAV), and such initial activation of STAT2 was independent of type I IFNs and JAK kinases. Furthermore, it was observed that the early activation of STAT2 during viral infection was mainly regulated by the RIG-I/MAVS-dependent pathway. Disruption of STAT2 phosphorylation at Tyr690 restrained antiviral response, as silencing STAT2 or blocking STAT2 Y690 phosphorylation suppressed the expression of several interferon-stimulated genes (ISGs), thereby facilitating viral replication. In vitro experiments using overexpression system or kinase inhibitors showed that several kinases including MAPK12 and Syk were involved in regulation of the early phosphorylation of STAT2 triggered by IAV infection. Moreover, when MAPK12 kinase was inhibited, expression of several ISGs was clearly decreased in cells infected with IAV at the early infection stage. Accordingly, inhibition of MAPK12 accelerated the replication of influenza virus in host. These results provide a better understanding of how initial activation of STAT2 and the early antiviral responses are induced by the viral infection.

Background and Objectives: Carbapenems have been the choice of antibiotics for the treatment of infections caused by multidrug-resistant bacteria. The main objective of this study was to determine the prevalence of carbapenemase (blaVIM and blaIMP) producing isolates among Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Materials and Methods: A total of 1,151 clinical samples were collected from the patients visiting Annapurna Neurological Institute and Allied Science and Annapurna Research Centre, Kathmandu, between June 2017 and January 2018. Antibiotic susceptibility testing (AST) was performed on the Enterobacteriaceae, P. aeruginosa and A. baumannii isolates using the Kirby-Bauer disk diffusion method. The modified Hodge test (MHT) was performed on the carbapenem-resistant isolates to confirm carbapenemase production. DNA was extracted and then screened for blaVIM and blaIMP genes by multiplex PCR. Results: Of the total 1,151 clinical samples, 253 (22.0%) showed positive growth. Of them, 226 (89.3%) were identified as Enterobacteriaceae, P. aeruginosa, and A. baumannii. Among the 226 isolates, 106 (46.9%) were multidrug-resistant. Out of the 106, 97 (91.5%) isolates showed resistance to at least one of the carbapenem used. Among the 97 carbapenem-resistant isolates, 67 (69.1%) showed the modified Hodge test (MHT) positive results. blaVIM and blaIMP were detected in 40 and 38 isolates respectively using multiplex PCR assay. Conclusion: This study determined a high prevalence of MDR and carbapenem resistance among Enterobacteriaceae, P. aeruginosa, and A. baumannii as detected by the presence of blaVIM and blaIMP genes. This study recommends the use of rapid and advanced diagnostic tools along with conventional phenotypic detection methods in the clinical settings for early detection and management of drug-resistant pathogens to improve treatment strategies.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

Background The existence of multidrug-resistant organisms, including extended-spectrum beta-lactamases (ESBLs), is on rise across the globe and is becoming a severe problem. Knowledge of the prevalence and antibiogram profile of such isolates is essential to develop an appropriate treatment methodology. This study aimed to study the prevalence of Gram-negative isolates exhibiting ESBL at a tertiary care hospital and study their antibiogram profile. Methods A cross-sectional study was conducted at Shahid Gangalal National Heart Centre, Kathmandu, Nepal, from June 2018 to November 2018. A total of 770 clinical samples were collected and identified using the conventional biochemical tests following the Clinical and Laboratory Standard Institute (CLSI) guidelines. Antimicrobial susceptibility testing (AST) was performed using the standardized Kirby-Bauer disk diffusion method. The screening test for ESBL producers was performed as recommended by the CLSI and the confirmatory test was performed phenotypically using the E-test. Results Out of the 92 isolates, 84 (91.3%) were multidrug-resistant, and 47 (51.1%) were found to be potential ESBL producers. Of these, 16 isolates were confirmed ESBL producers by the E-test. Escherichia coli and Klebsiella pneumoniae were the predominant isolates and were also the major ESBL producers. Besides polymyxin B (100% sensitive), meropenem and imipenem showed high efficacy against the ESBL producers. Conclusion Multidrug resistance was very high; however, ESBL production was low. Polymyxin B and carbapenems are the choice of drugs against ESBL producers but should be used only as the last line drugs.

Introduction Methicillin resistance, inducible clindamycin resistance (ICR), biofilm production, and increased minimum inhibitory concentration (MIC) of vancomycin in Staphylococcus aureus are major causes of antibiotic treatment failure and increased morbidity and mortality. The surveillance of such isolates and the study of their antimicrobial pattern are essential in managing the infections caused by these isolates. This study aimed to determine methicillin resistance, biofilm production, and ICR in S. aureus isolates from a tertiary care hospital in Kathmandu, Nepal. Materials and methods A total of 217 S. aureus isolated from different samples were processed following standard laboratory procedures. Antibiotic susceptibility testing was performed by the Kirby–Bauer disk diffusion technique. Methicillin-resistant S. aureus (MRSA) were identified by the cefoxitin disk diffusion test, and biofilm producers were examined using the microtiter plate technique. D-test and E-test were performed to determine inducible clindamycin resistance and minimum inhibitory concentration of vancomycin, respectively. Results Among the 217 S. aureus isolates, 78.3% were multidrug-resistant (MDR), 47.0% were MRSA, 62.2% were biofilm producers, and 50.7% showed ICR. All MRSA isolates exhibited MIC levels of vancomycin within the susceptible range. Biofilm producers and MRSA isolates showed elevated antimicrobial resistance. MRSA was significantly associated with MDR. Biofilm-producing and multidrug-resistant MRSA isolates showed significantly higher MIC levels of vancomycin (p = 0.0013 and p = 0.0001) isolates. Conclusion High multidrug resistance, MRSA, and ICR in this study call for routine evaluation of antibiotic susceptibility patterns of S. aureus. Vancomycin can be used to treat serious staphylococcal infections. Clindamycin should be prescribed only after performing the D-test. Drugs like teicoplanin, chloramphenicol, doxycycline, amikacin, and levofloxacin can treat MRSA infections.

Background and Objectives: Carbapenems have been the choice of antibiotics for the treatment of infections caused by multidrug-resistant bacteria. The main objective of this study was to determine the prevalence of carbapenemase (bla VIM and bla IMP ) producing isolates among Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Materials and Methods: A total of 1,151 clinical samples were collected from the patients visiting Annapurna Neurological Institute and Allied Science and Annapurna Research Centre, Kathmandu, between June 2017 and January 2018. Antibiotic susceptibility testing (AST) was performed on the Enterobacteriaceae, P. aeruginosa and A. baumannii isolates using the Kirby-Bauer disk diffusion method. The modified Hodge test (MHT) was performed on the carbapenem-resistant isolates to confirm carbapenemase production. DNA was extracted and then screened for bla VIM and bla IMP genes by multiplex PCR. Results: Of the total 1,151 clinical samples, 253 (22.0%) showed positive growth. Of them, 226 (89.3%) were identified as Enterobacteriaceae, P. aeruginosa, and A. baumannii. Among the 226 isolates, 106 (46.9%) were multidrug-resistant. Out of the 106, 97 (91.5%) isolates showed resistance to at least one of the carbapenem used. Among the 97 carbapenem-resistant isolates, 67 (69.1%) showed the modified Hodge test (MHT) positive results. bla VIM and bla IMP were detected in 40 and 38 isolates respectively using multiplex PCR assay. Conclusion: This study determined a high prevalence of MDR and carbapenem resistance among Enterobacteriaceae, P. aeruginosa, and A. baumannii as detected by the presence of bla VIM and bla IMP genes. This study recommends the use of rapid and advanced diagnostic tools along with conventional phenotypic detection methods in the clinical settings for early detection and management of drug-resistant pathogens to improve treatment strategies.

Rai is an indigenous people and decedent of Kirati dynasty, inhabitant of eastern part of Nepal. It is known as Kirat Pradesh before the unification of Nepal. Now, Kirat Pradesh is became political word in Nepal for name of province number 1 but not endorse till present. The Chamling Rai society is comprised different interdependent parts and units as like religion, culture, economy, polity, educational etc. Kirat religion is a part of Rai community constituted by the different units and interdepended among different parts. The Chamling word Nachhung (shaman) is called priest of the Kirat religion. So, this article focuses on the Nachhung who is the Rai priest, shaman and healer as functional unit of theRai society. The main research questions if how the Nachhung plays function as the being part of Rai society and contribute to existence of Rai society as whole. It explores the interdependence of Nachhung on other parts like rite and ritual, marriage, feast and festival, community, health, social and religious activities.

Introduction: Neonatal sepsis is the commonest cause of neonatal morbidity and mortality and remains a major public health problem especially in developing countries. It is one of the most common causes for admission to neonatal units. The objective of this study was to evaluate the cost of care of neonates admitted in Neonatal Intensive Care Unit. It also compared the cost of care of neonates with sepsis and those with non-sepsis along with the duration of hospital stay and its correlation. Method: A hospital based prospective cross-sectional observational study was carried out over a period of one year. All the neonates admitted at NICU and fulfilling the inclusion criteria formed the study population. Total cost was calculated as the summation of direct and indirect cost. Normally distributed data was analyzed using the Student’s t-test, non-normally distributed data using Mann-Whitney U test. P-value < 0.05 was taken to be statistically significant. Result: Direct cost comprises more than two third of the cost. The median total cost of care of neonates admitted in NICU was USD 222.66 (Range 169.52-280.03). The cost for the ones with sepsis was USD 226.30 (Range 172.19-291.34) and 174.02 (Range 99.67-221.96) in non-sepsis. The mean duration of stay in NICU of the ones having sepsis was 6.6 days and 4.4 days in non-sepsis. Conclusion: The median total cost of care of neonates admitted in NICU was USD 222.66 (Range 169.52-280.03). The duration of stay and the total cost of treatment with sepsis are higher than those with non-sepsis.

In this paper, we address one of the long-standing psychological disorders-seizure and the classification of patients as susceptible to seizure or healthy subjects. The classification is based on the EEG (electroencephalogram) recordings provided, by deploying the LSTM (long short-term memory) neural network architecture. The Temple University Hospital (TUH) EEG corpus dataset is selected as the dataset to be worked upon throughout this paper. The TUH EEG corpus is an open and large dataset, which undergoes frequent updating. Along with the EEG recordings, the session records also contain a detailed text report describing the medical history and the current condition of the patient as well. Another model, trained to utilize the NLP (natural language processing) features, approves the classification performed by the neural network on the EEG recordings. The proposed framework then undergoes evaluation on the validation dataset. The accuracy achieved by the framework is 73.16% on EEG data and 64.86% on text data.

Objective To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. Design Observational cohort study. Setting A total of 49 hospitals across the United Kingdom between 2011 and 2016. Participants Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. Methods Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. Intervention None. Main Outcome Measure Rates of thyroid dysfunction. Results Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). Conclusions The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

Spleen tyrosine kinase (Syk) has recently come forth as a critical regulator of innate immune response. Previous studies identify Syk as a key kinase for STAT1 activation at the early stage of influenza A virus (IAV) infection that is involved in initial antiviral immunity. However, the involvement of Syk in host antiviral immunity during the late phase of IAV infection and its effect on pathogenesis of the virus remain unknown. Here, we found through time course studies that Syk restrained antiviral immune response at the late stage of IAV infection, thereby promoting viral replication. Depletion of Syk suppressed IAV replication in vitro, whereas ectopic expression of Syk facilitated viral replication. Moreover, Syk-deficient mice were employed, and we observed that knockout of Syk rendered mice more resistant to IAV infection, as evidenced by a lower degree of lung injury, slower body weight loss, and an increased survival rate of Syk knockout mice challenged with IAV. Furthermore, we revealed that Syk repressed the interferon response at the late stage of viral infection. Loss of Syk potentiated the expression of type I and III interferons in both Syk-depleted cells and mice. Mechanistically, Syk interacted with TBK1 and modulated its phosphorylation status, thereby impeding TBK1 activation and restraining innate immune signaling that governs interferon response. Together, these findings unveil a role of Syk in temporally regulating host antiviral immunity and advance our understanding of complicated mechanisms underlying regulation of innate immunity against viral invasion. IMPORTANCE Innate immunity must be tightly controlled to eliminate invading pathogens while avoiding autoimmune or inflammatory diseases. Syk is essential for STAT1 activation at the early stage of IAV infection, which is critical for initial antiviral responses. Surprisingly, here a time course study showed that Syk suppressed innate immunity during late phases of IAV infection and thereby promoted IAV replication. Syk deficiency enhanced the expression of type I and III interferons, inhibited IAV replication, and rendered mice more resistant to IAV infection. Syk impaired innate immune signaling through impeding TBK1 activation. These data reveal that Syk participates in the initiation of antiviral defense against IAV infection and simultaneously contributes to the restriction of innate immunity at the late stage of viral infection, suggesting that Syk serves a dual function in regulating antiviral responses. This finding provides new insights into complicated mechanisms underlying interaction between virus and host immune system.

Porcine circovirus-associated disease (PCVAD), caused by porcine circovirus type 2 (PCV2), has ravaged the pig industry, causing huge economic loss. At present, PCV2b and PCV2d are highly prevalent genotypes worldwide, while in China, in addition to PCV2b and PCV2d, a newly emerged PCV2e genotype detected in the Fujian province has attracted attention, indicating that PCV2 genotypes in China are more abundant. A preliminary study was conducted to better understand the genetic diversity and prevalence of PCV2 genotypes in southern China. We collected 79 random lung samples from pigs with respiratory signs, from 2018 to 2021. We found a PCV2-positivity rate of 29.1%, and frequent co-infections of PCV2 with PCV3, Streptococcus suis (S. suis), and other porcine pathogens. All PCV2-positive samples were sequenced and subjected to whole-genome analysis. Phylogenetic analysis, based on the PCV2 ORF2 gene and complete genomes, found that PCV2 strains identified in this study belonged to genotypes PCV2a (1), PCV2b (6), PCV2d (10), and PCV2e (6). Importantly, PCV2e was identified for the first time in some provinces, including Guangdong and Jiangxi. Additionally, we found two positively selected sites in the ORF2 region, located on the previously reported antigenic epitopes. Moreover, codon 63, one of the positively selected sites, has different types of amino acids in different genotypes. In conclusion, this study shows that PCV2e is an emerging genotype circulating in southern China, which warrants urgent, specific surveillance to aid the development of prevention and control strategies in China.

African swine fever is one of the most devastating swine diseases caused by African swine fever virus (ASFV). Although ASFV encodes more than 160 viral proteins, the implication of a majority of ASFV proteins in regulating host immunity is yet to be explored, and the mechanisms of immune evasion by ASFV proteins are largely unknown. Here, we report that the I226R protein of ASFV significantly suppressed innate immune responses. The ectopic expression of ASFV I226R in 293T cells significantly inhibited the activation of interferon-stimulated response element promoters triggered by Sendai virus (SeV), poly(I:C), or cyclic GMP-AMP synthase (cGAS)/STING. The I226R protein caused a significant decrease in the expression of interferons and interferon-stimulating genes in cells infected with SeV. Similar results were obtained from experiments using I226R-overexpressed PK15 and 3D4/21 cells stimulated with vesicular stomatitis virus. We observed that I226R inhibited the activation of both nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). Furthermore, it was shown that overexpression of I226R suppressed IRF3 activation and caused the degradation of NF-κB essential modulator (NEMO) protein. The I226R-induced NEMO degradation could be prevented by treatment with MG132, a proteasome inhibitor. Together, these results reveal that the ASFV I226R protein impairs antiviral responses, likely through multiple mechanisms including the suppression of NF-κB and IRF3 activation, to counteract innate immune responses during the viral infection.

Background Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Control of TB is lingering by the lack of diagnostic tests that are simple, rapid, yet accurate. Thus, smear-negative pulmonary TB often misses the diagnosis. The study evaluated the performance of GeneXpert MTB/RIF assay for the detection of Mycobacterium tuberculosis (MTB). Methods The study was carried out from June to December 2016 in Nepal Tuberculosis Center, Bhaktapur, Nepal. A total of 173 sputum samples were collected and processed by microscopy [Auramine-O staining and Ziehl–Neelsen (ZN) staining], followed by GeneXpert MTB/RIF assay and culture in Lowenstein-Jensen (LJ) medium. Results Of 173 sputum samples, 162 (93.6%) were smear-negative. Of 162 smear-negative sputum samples, 35 (21.6%) were confirmed to have MTB by culture, and 31 (19.1%) by GeneXpert MTB/RIF assay. Of 31 GeneXpert-positive samples, 25 (80.6%) were susceptible, 4 (12.9%) were resistant, and 2 (6.45%) were intermediate to rifampicin. The sensitivity, specificity, positive predictive value, and negative predictive value of GeneXpert MTB/RIF assay for smear-negative sputum samples were 74.3%, 96.6%, 86.7%, and 92%, respectively. The GeneXpert MTB/RIF has a substantial diagnostic agreement of 90.91% with culture (Cohen’s Kappa coefficient = 0.73). Conclusion The diagnostic performance of GeneXpert MTB/RIF assay was almost on par with culture, and thus can be relied upon for MTB detection in smear-negative sputum samples.

Long noncoding RNAs (lncRNAs) are involved in numerous cellular processes. Increasing evidence suggests that some lncRNAs function in immunity through various complex mechanisms. However, implication of a large fraction of lncRNAs in antiviral innate immunity remains uncharacterized. Here, we identified an lncRNA called lncRNA IFITM4P that was transcribed from interferon-induced transmembrane protein 4 pseudogene (IFITM4P), a pseudogene belonging to the interferon-induced transmembrane protein (IFITM) family. We found that expression of lncRNA IFITM4P was significantly induced by infection with several viruses, including influenza A virus (IAV). Importantly, lncRNA IFITM4P acted as a positive regulator of innate antiviral immunity. Ectopic expression of lncRNA IFITM4P significantly suppressed IAV replication in vitro, whereas IFITM4P deficiency promoted viral production. We further observed that expression of lncRNA IFITM4P was upregulated by interferon (IFN) signaling during viral infection, and altering the expression of this lncRNA had significant effects on the mRNA levels of several IFITM family members, including IFITM1, IFITM2, and IFITM3. Moreover, lncRNA IFITM4P was identified as a target of the microRNA miR-24-3p, which represses mRNA of IFITM1, IFITM2, and IFITM3. The experiments demonstrated that lncRNA IFITM4P was able to cross-regulate the expression of IFITM family members as a competing endogenous RNA (ceRNA), leading to increased stability of these IFITM mRNAs. Together, our results reveal that lncRNA IFITM4P, as a ceRNA, is involved in innate immunity against viral infection through the lncRNA IFITM4P–miR-24-3p–IFITM1/2/3 regulatory network. IMPORTANCE lncRNAs play important roles in various biological processes, but their involvement in host antiviral responses remains largely unknown. In this study, we revealed that the pseudogene IFITM4P belonging to the IFITM family can transcribe a functional long noncoding RNA termed lncRNA IFITM4P. Importantly, results showed that lncRNA IFITM4P was involved in innate antiviral immunity, which resembles some interferon-stimulated genes (ISGs). Furthermore, lncRNA IFITM4P was identified as a target of miR-24-3p and acts as a ceRNA to inhibit the replication of IAV through regulating the mRNA levels of IFITM1, IFITM2, and IFITM3. These data provide new insight into the role of a previously uncharacterized lncRNA encoded by a pseudogene in the host antiviral response and a better understanding of the IFITM antiviral network.

Eukaryotic translation initiation factor 4B (eIF4B) plays an important role in mRNA translation initiation, cell survival and proliferation in vitro. However, its function in vivo is poorly understood. Here, we identified that eIF4B knockout (KO) in mice led to embryonic lethality, and the embryos displayed severe liver damage. Conditional KO (CKO) of eIF4B in adulthood profoundly increased the mortality of mice, characterized by severe pathological changes in several organs and reduced number of peripheral blood lymphocytes. Strikingly, eIF4B CKO mice were highly susceptible to viral infection with severe pulmonary inflammation. Selective deletion of eIF4B in lung epithelium also markedly promoted replication of influenza A virus (IAV) in the lung of infected animals. Furthermore, we observed that eIF4B deficiency significantly enhanced the expression of several important inflammation-associated factors and chemokines, including serum amyloid A1 (Saa1), Marco, Cxcr1, Ccl6, Ccl8, Ccl20, Cxcl2, Cxcl17 that are implicated in recruitment and activation of neutrophiles and macrophages. Moreover, the eIF4B-deficient mice exhibited impaired natural killer (NK) cell-mediated cytotoxicity during the IAV infection. Collectively, the results reveal that eIF4B is essential for mouse survival and host antiviral responses, and establish previously uncharacterized roles for eIF4B in regulating normal animal development and antiviral immunity in vivo.

Historically, a lack of methodologically strong and generalizable studies has limited policymakers fromrecommending the use of progesterone supplementation to improve outcomes in women at high risk of miscarriage. The PROMISE and PRISM trials were carried out to rectify this and generate robust evidence on the role of progesterone supplementation to prevent miscarriage. This review aims to evaluate the PROMISE and PRISM trials and their impact on collective academic understanding of the use of progesterone supplementation for miscarriage prevention, as well as to provide recommendations for clinical practice. The PROMISE trial was a randomized double-blind, placebo-controlled study that included 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% increase in live birth rate with progesterone supplementation; however, the P value associated with this finding was 0.45. A post hoc subgroup analysis was performed with cohorts stratified according to number of previous miscarriages that revealed a trend for greater benefit with increasing number of previous miscarriages. Small sample sizes in this subgroup analysis resulted in a P value of 0.41; however, these results were hypothesis-generating that a biological gradient existed with respect to improved benefit of progesterone treatment among women with an increasing number of prior miscarriages. The PRISMtrial was a randomized, double-blind, placebo-controlled study that involved 4153 women from48 hospitals in the United Kingdom and noted a 3% increase in live birth rate with vaginal micronized progesterone; however, the P value associated with this finding was 0.08. To followup on the gradient effect observed in the PROMISE trial, this study included a prespecified subgroup analysis analyzing the number of previous miscarriages with population split into 3 subgroups: women with zero prior miscarriages, women with 1 to 2 prior miscarriages, and women with 3 or more prior miscarriages. Among women with 1 or more priormiscarriages and bleeding in the current pregnancy, the live birth rate was 75%with progesterone versus 70% with placebo (risk ratio, 1.09; 95% confidence interval, 1.03 1.15; P = 0.003). Among women with 3 or more prior miscarriages and bleeding in the current pregnancy, live birth rate was 72% with progesterone versus 57% with placebo (risk ratio, 1.28; 95% confidence interval, 1.08 1.51; P = 0.004). Guidelines for interpretation of subgroup analyses translate into 11 criteria to assess credibility and therefore clinical applicability; 5 on design, 2 on analysis, and 4 on context. The PRISM trials subgroup analysis meets all 11 criteria in women with dual risk factors of previous miscarriage and current pregnancy bleeding, suggesting the subgroup effect of a gradient existing in the context of improving live birth rate with progesterone treatment is highly plausible. Given biologic plausibility, lack of short-term safety concerns, and observed positive treatment effect, providers should consider offering women with vaginal bleeding and a history of 1 or more previous miscarriages a course of treatment with vaginal micronized progesterone 400 mg twice daily.

The Himalayas, especially the Everest region, are highly sensitive to climate change. Although there are research works on this region related to cryospheric work, the ecological understandings of the alpine zone and climate impacts are limited. This study aimed to assess the changes in surface water including glacier lake and streamflow and the spatial and temporal changes in alpine vegetation and examine their relationships with climatic factors (temperature and precipitation) during 1995–2019 in the Everest region and the Dudh Koshi river basin. In this study, Landsat time-series data, European Commission’s Joint Research Center (JRC) surface water data, ECMWF Reanalysis 5th Generation (ERA5) reanalysis temperature data, and meteorological station data were used. It was found that the glacial lake area and volume are expanding at the rates of 0.0676 and 0.0198 km3/year, respectively, the average annual streamflow is decreasing at the rate of 2.73 m3/s/year. Similarly, the alpine vegetation greening as indicated by normalized difference vegetation index (NDVI) is increasing at the rate of 0.00352 units/year. On the other hand, the annual mean temperature shows an increasing trend of 0.0329 °C/year, and the annual precipitation also shows a significant negative monotonic trend. It was also found that annual NDVI is significantly correlated with annual temperature. Likewise, the glacial lake area expansion is strongly correlated with annual minimum temperature and annual precipitation. Overall, we found a significant alteration in the alpine ecosystem of the Everest region that could impact on the water–energy–food nexus of the Dudh Koshi river basin.

Aim Although carbapenem is the last-resort drug for treating drug-resistant Gram-negative bacterial infections, prevalence of carbapenem-resistant bacteria has substantially increased worldwide owing to irrational use of antibiotics particularly in developing countries like Nepal. Therefore, this study was aimed to determine the prevalence of carbapenemase-producing K. pneumoniae and to detect the carbapenemase genes (blaNDM-2 and blaOXA-48) in at a tertiary care hospital in Nepal. Materials and methods A hospital-based cross-sectional study was carried out from June 2018 to January 2019 at the Microbiology Laboratory of Annapurna Neurological Institute and Allied Sciences, Kathmandu, Nepal. Different clinical samples were collected and cultured in appropriate growth media. Biochemical tests were performed for the identification of K. pneumoniae. Antibiotic susceptibility testing (AST) was performed by the Kirby–Bauer disc diffusion method. The modified Hodge test (MHT) was performed to detect carbapenemase producers. The plasmid was extracted by the modified alkaline hydrolysis method. Carbapenemase-producing K. pneumoniae were further confirmed by detecting blaNDM-2 and blaOXA-48 genes by PCR using specific forward and reverse primers followed by gel electrophoresis. Results Out of the total 720 samples, 38.9% (280/720) were culture positive. K. pneumoniae was the most predominant isolate 31.4% (88/280). Of 88 K. pneumoniae isolates, 56.8% (50/88) were multi-drug resistant (MDR), and 51.1% (45/88) were MHT positive. Colistin showed the highest sensitivity (100%; 88/88), followed by tigecycline (86.4%; 76/88). blaNDM-2 and blaOXA-48 genes were detected in 24.4% (11/45) and 15.5% (7/45) of carbapenemase-producing K. pneumoniae isolates, respectively. Conclusion The rate of MDR and carbapenemase production was high in the K. pneumoniae isolates. Colistin and tigecycline could be the drug of choice for the empirical treatments of MDR and carbapenemase-producing K. pneumoniae. Our study provides a better understanding of antibiotic resistance threat and enables physicians to select the most appropriate antibiotics.

Viral infections can cause rampant disease in human beings, ranging from mild to acute, that can often be fatal unless resolved. An acute viral infection is characterized by sudden or rapid onset of disease, which can be resolved quickly by robust innate immune responses exerted by the host or, instead, may kill the host. Immediately after viral infection, elements of innate immunity, such as physical barriers, various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, provide the first line of defense for viral clearance. Innate immunity not only plays a critical role in rapid viral clearance but can also lead to disease progression through immune-mediated host tissue injury. Although elements of antiviral innate immunity are armed to counter the viral invasion, viruses have evolved various strategies to escape host immune surveillance to establish successful infections. Understanding complex mechanisms underlying the interaction between viruses and host’s innate immune system would help develop rational treatment strategies for acute viral infectious diseases. In this review, we discuss the pathogenesis of acute infections caused by viral pathogens and highlight broad immune escape strategies exhibited by viruses.

Influenza A virus (IAV), a highly infectious respiratory pathogen, remains a major threat to global public health. Numerous long non-coding RNAs (lncRNAs) have been shown to be implicated in various cellular processes. Here, we identified a new lncRNA termed RIG-I-dependent IAV-upregulated noncoding RNA (RDUR), which was induced by infections with IAV and several other viruses. Both in vitro and in vivo studies revealed that robust expression of host RDUR induced by IAV was dependent on the RIG-I/NF-κB pathway. Overexpression of RDUR suppressed IAV replication and downregulation of RDUR promoted the virus replication. Deficiency of mouse RDUR increased virus production in lungs, body weight loss, acute organ damage and consequently reduced survival rates of mice, in response to IAV infection. RDUR impaired the viral replication by upregulating the expression of several vital antiviral molecules including interferons (IFNs) and interferon-stimulated genes (ISGs). Further study showed that RDUR interacted with ILF2 and ILF3 that were required for the efficient expression of some ISGs such as IFITM3 and MX1. On the other hand, we found that while NF-κB positively regulated the expression of RDUR, increased expression of RDUR, in turn, inactivated NF-κB through a negative feedback mechanism to suppress excessive inflammatory response to viral infection. Together, the results demonstrate that RDUR is an important lncRNA acting as a critical regulator of innate immunity against the viral infection.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

BackgroundThe existence of multi-drug resistance organisms, including extended-spectrum beta-lactamases (ESBLs), is on the rise and is becoming a severe problem. Knowledge of the prevalence and antibiogram profile of such isolates is essential to develop an appropriate treatment methodology. This study aimed to study the prevalence of Gram-negative isolates exhibiting ESBL at a tertiary care hospital and study their antibiogram profile.MethodsA cross-sectional study was conducted at Shahid Gangalal National Heart Centre, Kathmandu, Nepal, from June 2018 to November 2018. A total of 770 clinical samples were collected and identified by using the conventional biochemical tests following the Clinical and Laboratory Standard Institute (CLSI) guidelines. Antimicrobial susceptibility testing (AST) was performed using the Kirby Bauer disc diffusion method. The screening test for ESBL producers was performed as recommended by the CLSI and the confirmatory test was performed phenotypically using the E-test.ResultsOut of 92 isolates, 84 (91.3%) isolates were multidrug resistant, and 47 (51.1%) isolates were found to be potential ESBL producers. Of these, 16 isolates were confirmed ESBL producers by the E-test. Escherichia coli and Klebsiella pneumoniae were the predominant isolates and were also the major ESBL producers. Besides polymyxin B (100% sensitive), meropenem and imipenem showed high efficacy against the ESBL producers.ConclusionMultidrug resistance was very high, however, ESBL production was low. Polymyxin B and carbapenems are the choice of drugs against ESBL producers but should be used only as the last line drugs.