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BACKGROUND: During neurogenesis, growing axons must navigate through the complex extracellular environment and make correct synaptic connections for the proper functioning of neural circuits. The mechanisms underlying the formation of functional neural networks are still only partially understood. RESULTS: Here we analyzed the role of a novel gene si:ch73-364h19.1/drish in the neural and vascular development of zebrafish embryos. We show that drish mRNA is expressed broadly and dynamically in multiple cell types including neural, glial, retinal progenitor and vascular endothelial cells throughout the early stages of embryonic development. To study Drish function during embryogenesis, we generated drish genetic mutant using CRISPR/Cas9 genome editing. drish loss-of-function mutant larvae displayed defects in early retinal ganglion cell, optic nerve and the retinal inner nuclear layer formation, as well as ectopic motor axon branching. In addition, drish mutant adults exhibited deficient retinal outer nuclear layer and showed defective light response and locomotory behavior. However, vascular patterning and blood circulation were not significantly affected. CONCLUSIONS: Together, these data demonstrate important roles of zebrafish drish in the retinal ganglion cell, optic nerve and interneuron development and in spinal motor axon branching.
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Axônios , Neurogênese , Células Ganglionares da Retina , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Peixe-Zebra/genética , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/fisiologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Axônios/metabolismo , Axônios/fisiologia , Neurogênese/genética , Neurogênese/fisiologia , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Embrião não Mamífero/metabolismo , Retina/metabolismo , Retina/embriologiaRESUMO
Previous studies have suggested that the endocardium contributes to hematopoiesis in murine embryos, although definitive evidence to demonstrate the hematopoietic potential of the endocardium is still missing. Here, we use a zebrafish embryonic model to test the emergence of hematopoietic progenitors from the endocardium. By using a combination of expression analysis, time-lapse imaging, and lineage-tracing approaches, we demonstrate that myeloid cells emerge from the endocardium in zebrafish embryos. Inhibition of Etv2/Etsrp or Scl/Tal1, two known master regulators of hematopoiesis and vasculogenesis, does not affect the emergence of endocardial-derived myeloid cells, while inhibition of Hedgehog signaling results in their reduction. Single-cell RNA sequencing analysis followed by experimental validation suggests that the endocardium is the major source of neutrophilic granulocytes. These findings will promote our understanding of alternative mechanisms involved in hematopoiesis, which are likely to be conserved between zebrafish and mammalian embryos.
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Proteínas Hedgehog , Peixe-Zebra , Animais , Camundongos , Endocárdio , Células Sanguíneas , Embrião de Mamíferos , MamíferosRESUMO
Introduction: The most prevalent endocrine cancer in the world is thyroid cancer, and its incidence is on the rise. The distinction between benign and malignant thyroid nodules must be made, which is why fine needle aspiration cytology of thyroid lesion is necessary and required. This study aimed to find out the prevalence of thyroid malignancy among fine needle aspiration cytology of thyroid lesions in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among fine needle aspiration cytology of thyroid lesions in a tertiary care centre after obtaining ethical approval from the Institutional Review Committee. Data from 13 April 2020 to 13 April 2023 was collected between 19 May 2023 to 19 June 2023. All the patients with complete hospital record data were included in this study. However, repetitive fine needle aspiration cytology of thyroid lesion were excluded from the study. Fine needle aspiration cytology diagnoses were categorized in this study as per the Bethesda system for reporting thyroid cytopathology. The point estimate was calculated at a 95% Confidence Interval. Results: Among 398 fine needle aspiration cytology of thyroid lesions, thyroid malignancy was seen in 12 (3.02%) (1.34-4.70, 95% Confidence Interval) patients. Conclusions: The prevalence of thyroid malignancy was found to be lower than other studies done in similar settings. Keywords: cytology; malignancy; prevalence; thyroid.
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Neoplasias da Glândula Tireoide , Humanos , Biópsia por Agulha Fina , Centros de Atenção Terciária , Estudos Transversais , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Estudos RetrospectivosRESUMO
Blood vessels in different vascular beds vary in size, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vessel size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow, eventually leading to the DA collapse. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA size in she mutants correlated with an increased endothelial expression of claudin 5a (cldn5a), which encodes a protein enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates vessel and lumen size during vascular tubulogenesis.
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Peixe-Zebra , Domínios de Homologia de src , Animais , Humanos , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , China , Etnicidade , Transdução de Sinais/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Claudina-5RESUMO
OBJECTIVES: Active case finding (ACF) is an important tuberculosis (TB) intervention in high-burden settings. However, empirical evidence garnered from field data has been equivocal about the long-term community-level impact, and more data at a finer geographic scale and data-informed methods to quantify their impact are necessary. METHODS: Using village development committee (VDC)-level data on TB notification and demography between 2016 and 2017 in four southern districts of Nepal, where ACF activities were implemented as a part of the IMPACT-TB study between 2017 and 2019, we developed VDC-level transmission models of TB and ACF. Using these models and ACF yield data collected in the study, we estimated the potential epidemiological impact of IMPACT-TB ACF and compared its efficiency across VDCs in each district. RESULTS: Cases were found in the majority of VDCs during IMPACT-TB ACF, but the number of cases detected within VDCs correlated weakly with historic case notification rates. We projected that this ACF intervention would reduce the TB incidence rate by 14% (12-16) in Chitwan, 8.6% (7.3-9.7) in Dhanusha, 8.3% (7.3-9.2) in Mahottari and 3% (2.5-3.2) in Makwanpur. Over the next 10 years, we projected that this intervention would avert 987 (746-1282), 422 (304-571), 598 (450-782) and 197 (172-240) cases in Chitwan, Dhanusha, Mahottari and Makwanpur, respectively. There was substantial variation in the efficiency of ACF across VDCs: there was up to twofold difference in the number of cases averted in the 10 years per case detected. CONCLUSION: ACF data confirm that TB is widely prevalent, including in VDCs with relatively low reporting rates. Although ACF is a highly efficient component of TB control, its impact can vary substantially at local levels and must be combined with other interventions to alter TB epidemiology significantly.
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Programas de Rastreamento , Tuberculose , Humanos , Nepal/epidemiologia , Programas de Rastreamento/métodos , Tuberculose/epidemiologia , IncidênciaRESUMO
Blood vessels in different vascular beds vary in lumen diameter, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vascular lumen size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA lumen, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA lumen in she mutants correlated with an increased endothelial expression of claudin 5a and 5b (cldn5a / cldn5b), which encode proteins enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA lumen size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates lumen size during vascular tubulogenesis.
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This study compares the yield and additionality of community-based active tuberculosis (TB) active case-finding strategies using either smear microscopy or GeneXpert as the TB diagnostic test. Active case-finding strategies screened social contacts of index cases and high-risk groups in four districts of Nepal in July 2017-2019. Two districts (Chitwan and Dhanusha) applied GeneXpert testing and two districts (Makwanpur and Mahotarri) used smear microscopy. Two control districts implemented standard national TB program activities. Districts implementing GeneXpert testing screened 23,657 people for TB, tested 17,114 and diagnosed 764 TB cases, producing a yield of 4.5%. Districts implementing smear microscopy screened 19,961 people for TB, tested 13,285 and diagnosed 437 cases, producing a yield of 3.3%. The screening numbers required were 31 for GeneXpert and 45.7 for smear districts. The test numbers required were 22.4 and 30.4 for GeneXpert and smear. Using the TB REACH additionality method, social contact tracing for TB through GeneXpert testing contributed to a 20% (3958/3322) increase in district-level TB notifications, smear microscopy 12.4% (3146/2798), and -0.5% (2553/2566) for control districts. Therefore, social contact tracing of TB index cases using GeneXpert testing should be implemented throughout Nepal within the TB FREE initiative to close the notification gap and accelerate progress toward END TB strategy targets.
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Giant appendicoliths are rare appendicoliths with the largest diameter of more than 2 cm. It can increase the risk of complications such as perforation or abscess formation. This is a case of an uncommon definitive pathology diagnosed for a right iliac fossa calcification with a rare transoperative finding.
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BACKGROUND: The WHO recommends oral calcium supplementation (1.5-2.0 g) in pregnant women to reduce the risk of pre-eclampsia living in areas with low dietary calcium intake. Although maternal mortality is high in Nepal and eclampsia causes at least 20% of maternal deaths, implementing WHO recommendations would be a major undertaking. OBJECTIVE: This review aimed to assess whether the current evidence supports the blanket supplementation of calcium to prevent pre-eclampsia among pregnant women in Nepal. METHODS: We used a structured approach to appraise the evidence for calcium supplementation in Nepal. We identified what may influence the impact of calcium supplementation in Nepal and conducted a situation analysis in the country covering maternal mortality, pre-eclampsia occurrence, and existing government policy provisions for supplementation. We also consulted with experts and government officials to explore their perspectives and experience on supplementation. We then used AMSTAR (A MeaSurement Tool to Assess Systematic Reviews) to appraise the Cochrane Systematic Review of calcium supplementation. Finally, we used these data in a GRADE (Grading of Recommendations Assessment, Development and Evaluation)-Evidence to Decision framework to reach a policy recommendation. RESULTS: Our assessment of the Cochrane Review showed that the recommendation made by the WHO is based on weak evidence and trial findings that are not consistent between studies. The Cochrane Review found low certainty of the evidence for benefit (reduction in pre-eclampsia and maternal mortality). Conversely, there is a high certainty of the evidence of undesirable effects (HELLP [haemolysis, elevated liver enzymes and low platelets] syndrome) although this is uncommon. The likely absolute reduction in maternal deaths projected to Nepal was estimated to be low, while the implementation costs were high. Stakeholders also raised several concerns regarding feasibility, acceptability, appropriate dosing, and risk communication. CONCLUSIONS: This review concludes that the blanket supplementation of calcium cannot be recommended in Nepal. A better approach may be to identify high-risk pregnant women and manage their antenatal visits and delivery to prevent mortality from pre-eclampsia.
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Morte Materna , Pré-Eclâmpsia , Cálcio , Cálcio da Dieta , Suplementos Nutricionais , Feminino , Humanos , Nepal , Políticas , Pré-Eclâmpsia/prevenção & controle , Gravidez , GestantesRESUMO
Vascular endothelial cells exhibit substantial phenotypic and transcriptional heterogeneity which is established during early embryogenesis. However, the molecular mechanisms involved in establishing endothelial cell diversity are still not well understood. Zebrafish has emerged as an advantageous model to study vascular development. Despite its importance, the single-cell transcriptomic profile of vascular endothelial cells during zebrafish development is still missing. To address this, we applied single-cell RNA-sequencing (scRNA-seq) of vascular endothelial cells isolated from zebrafish embryos at the 24 hpf stage. Six distinct clusters or subclusters related to vascular endothelial cells were identified which include arterial, two venous, cranial, endocardial and endothelial progenitor cell subtypes. Furthermore, we validated our findings by characterizing novel markers for arterial, venous, and endocardial cells. We experimentally confirmed the presence of two transcriptionally different venous cell subtypes, demonstrating heterogeneity among venous endothelial cells at this early developmental stage. This dataset will be a valuable resource for future functional characterization of vascular endothelial cells and interrogation of molecular mechanisms involved in the establishment of their heterogeneity and cell-fate decisions.
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Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Células Endoteliais , Análise de Célula Única , Transcriptoma , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
INTRODUCTION AND IMPORTANCE: Colon cancer presenting as spontaneous enterocutaneous fistula are rare with only few cases reported in the literature. Such presentation signifies locally advanced disease with poorer outcomes. Enterocutaneous fistula increases morbidity and mortality in cancer and may potentially delay the definitive care. It poses a difficulty in management in terms of patient optimization, determining the type of resection (palliative or curative) and the operative timeline. CASE PRESENTATION: A 47â¯years old female presented with complaints of foul smelling discharge from a fistulous opening in right iliac fossa with occasional per rectal bleeding for the past six months. Imaging showed ascending colon mass breaching the peritoneum with fistulous tract opening into subcutaneous plane. Exploratory laparotomy with right hemicolectomy and en bloc resection was performed. CLINICAL DISCUSSION: Cutaneous fistula can be caused by traumatic, postoperative etiologies and about 20 % are of spontaneous etiologies. Colon cancer has the ability to mimic any abdominal disease with a wide spectrum of presentations. The locoregional extension from the bowel creates a passage of colonic contents to evacuate from the external opening. The fistulous tract of colon cancer is less likely to close spontaneously and may require surgical intervention following appropriate resuscitation. Due to features suggestive of bowel obstruction an early single stage surgery was performed in our case. CONCLUSION: There are no existing guidelines for colon cancer with colocutaneous fistula because they are the same for benign fistulas (resuscitation, control of output, eradication of the infection, nutritional optimization, surgery) along with a multidisciplinary oncology team approach.
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BACKGROUND: The World Health Organization has recommended Vitamin A supplementation for children in low- and middle-income countries for many years to reduce child mortality. Nepal still practices routine Vitamin A supplementation. We examined the potential current impact of these programs using national data in Nepal combined with an update of the mortality effect estimate from a meta-analysis of randomized controlled trials. METHODS: We used the 2017 Cochrane review as a template for an updated meta-analysis. We conducted fresh searches, re-applied the inclusion criteria, re-extracted the data for mortality and constructed a summary of findings table using GRADE. We applied the best estimate of the effect obtained from the trials to the national statistics of the country to estimate the impact of supplementation on under-five mortality in Nepal. RESULTS: The effect estimates from well-concealed trials gave a 9% reduction in mortality (Risk Ratio: 0.91, 95% CI 0.85 to 0.97, 6 trials; 1,046,829 participants; low certainty evidence). The funnel plot suggested publication bias, and a meta-analysis of trials published since 2000 gave a smaller effect estimate (Risk Ratio: 0.96, 95% CI 0.89 to 1.03, 2 trials, 1,007,587 participants), with the DEVTA trial contributing 55.1 per cent to this estimate. Applying the estimate from well-concealed trials to Nepal's under-five mortality rate, there may be a reduction in mortality, and this is small from 28 to 25 per 1000 live births; 3 fewer deaths (95% CI 1 to 4 fewer) for every 1000 children supplemented. CONCLUSIONS: Vitamin A supplementation may only result in a quantitatively unimportant reduction in child mortality. Stopping blanket supplementation seems reasonable given these data.
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Deficiência de Vitamina A , Vitamina A , Criança , Mortalidade da Criança , Suplementos Nutricionais , Humanos , Nepal/epidemiologia , Vitamina A/uso terapêutico , Deficiência de Vitamina A/tratamento farmacológico , Deficiência de Vitamina A/epidemiologia , Deficiência de Vitamina A/prevenção & controleRESUMO
Introduction and importance: The stump appendicitis is a rare complication with incidence of 1 in 50,000 appendectomy cases. Case presentation: Patient with a history of emergency open appendectomy one year back presented with symptoms as that of acute appendicitis like pain abdomen localized in right iliac fossa, nausea, vomiting and anorexia. Complete blood count showed leukocytosis. Clinical discussion: Aside from classical clinical symptoms similar to acute appendicitis other causes of acute abdominal pain were ruled out with clinical laboratory and radiological investigations. This creates a dilemma and delay in diagnosis if investigations are not done promptly. Conclusion: Due to prior surgical history of appendectomy and low index of suspicion, the diagnosis of stump appendicitis is often delayed which may result in serious complications like stump gangrene, perforation and peritonitis.
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BACKGROUND: The World Health Organization's End TB (tuberculosis) Strategy advocates social and economic support for TB-affected households but evidence from low-income settings is scarce. We will evaluate the feasibility and acceptability of a locally-appropriate socioeconomic support intervention for TB-affected households in Nepal. METHODS: We will conduct a pilot randomised-controlled trial with mixed-methods process evaluation in four TB-endemic, impoverished districts of Nepal: Pyuthan, Chitwan, Mahottari, and Morang. We will recruit 128 people with TB notified to the Nepal National TB Program (NTP) and 40 multisectoral stakeholders including NTP staff, civil-society members, policy-makers, and ASCOT (Addressing the Social Determinants and Consequences of Tuberculosis) team members. People with TB will be randomised 1:1:1:1 to four study arms (n=32 each): control; social support; economic support; and combined social and economic (socioeconomic) support. Social support will be TB education and peer-led mutual-support TB Clubs providing TB education and stigma-reduction counselling. Economic support will be monthly unconditional cash transfers during TB treatment with expectations (not conditions) of meeting NTP goals. At 0, 2, and 6 months following TB treatment initiation, participants will be asked to complete a survey detailing the social determinants and consequences of TB and their feedback on ASCOT. Complementary process evaluation will use focus group discussions (FGD), key informant interviews (KII), and a workshop with multi-sectoral stakeholders to consider the challenges to ASCOT's implementation and scale-up. A sample of ~100 people with TB is recommended to estimate TB-related costs. Information power is estimated to be reached with approximately 25 FGD and 15 KII participants. CONCLUSIONS: The ASCOT pilot trial will both generate robust evidence on a locally-appropriate, socioeconomic support intervention for TB-affected households in Nepal and inform a large-scale future ASCOT trial, which will evaluate the intervention's impact on catastrophic costs mitigation and TB outcomes. The trial is registered with the ISRCTN ( ISRCTN17025974).
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Cervical cancer is preventable and curable yet causes almost 2000 deaths in Nepali women each year. The present study aims to explore the feasibility and acceptability of a self-sampling-based approach for cervical cancer screening in urban and peri-urban Nepal and develop pathways for self-sampling using a co-design methodology. An iterative design approach was applied. Semi-structured in-depth interviews were conducted with 30 healthy women and four women who had had a prior cancer diagnosis on topics which included: sexual and reproductive health knowledge and human papillomavirus (HPV); use of the internet/social media platforms; their views regarding acceptability and usability of the self-sampling kit and the proposed user journey. Data collection was done between December 2020 and January 2021. Seven medical experts were also interviewed to explore the current service configuration for cervical cancer screening in Nepal. Knowledge regarding HPV and its association with cervical cancer was absent for the majority of participants. Although 70% (n = 21/30) had purchased items online previously, there was a general lack of trust in online shopping. Half of the women (n = 17/30; 56.7%) expressed a willingness to self-sample and provided recommendations to improve the clarity of the instructions. The proposed user journey was considered feasible in the urban area. There is a clear unmet need for information about HPV and alternative cervical screening options in Nepal. An online pathway for self-sampling service delivery to urban women is feasible but will need to be optimally designed to address barriers such as confidence in self-sampling and trust in online purchasing.
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Alphapapillomavirus , Neoplasias do Colo do Útero , Detecção Precoce de Câncer , Estudos de Viabilidade , Feminino , Humanos , Nepal , Papillomaviridae , Neoplasias do Colo do Útero/diagnósticoRESUMO
INTRODUCTION AND IMPORTANCE: Appendiceal neuroendocrine tumors (ANETs) are incidentally found in 0.2-0.7% of appendectomies for suspected appendicitis. CASE PRESENTATION: A 29-year-old female presented with pain in the right lower quadrant of her abdomen for the past 48 h. On emergency appendectomy for suspected acute appendicitis, a perforated appendix was found. Histopathological examination showed grade 1 (low) ANET. CLINICAL DISCUSSION: Appendiceal neuroendocrine neoplasms (ANENs) are commonly found at the tip of the appendix and are treated with appendectomy alone. For few ANENs located at the base, or small tumors (≤2 cm) infiltrating the submucosa, the muscularis, the subserosa layer or the mesoappendix, right hemicolectomy is recommended. However, no guidelines have been established concerning patients with appendiceal perforation in case of ANENs. CONCLUSION: Although rare, ANETs should be considered in the differential diagnosis of acute appendicitis. Since, ANETs are rarely diagnosed preoperatively, subsequent patient evaluation after appendectomy is crucial for management of the patient.
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OBJECTIVE: Psychosocial and economic (socioeconomic) barriers, including poverty, stigma and catastrophic costs, impede access to tuberculosis (TB) services in low-income countries. We aimed to characterise the socioeconomic barriers and facilitators of accessing TB services in Nepal to inform the design of a locally appropriate socioeconomic support intervention for TB-affected households. DESIGN: From August 2018 to July 2019, we conducted an exploratory qualitative study consisting of semistructured focus group discussions (FGDs) with purposively selected multisectoral stakeholders. The data were managed in NVivo V.12, coded by consensus and analysed thematically. SETTING: The study was conducted in four districts, Makwanpur, Chitwan, Dhanusha and Mahottari, which have a high prevalence of poverty and TB. PARTICIPANTS: Seven FGDs were conducted with 54 in-country stakeholders, grouped by stakeholders, including people with TB (n=21), community stakeholders (n=13) and multidisciplinary TB healthcare professionals (n=20) from the National TB Programme. RESULTS: The perceived socioeconomic barriers to accessing TB services were: inadequate TB knowledge and advocacy; high food and transportation costs; income loss and stigma. The perceived facilitators to accessing TB care and services were: enhanced championing and awareness-raising about TB and TB services; social protection including health insurance; cash, vouchers and/or nutritional allowance to cover food and travel costs; and psychosocial support and counselling integrated with existing adherence counselling from the National TB Programme. CONCLUSION: These results suggest that support interventions that integrate TB education, psychosocial counselling and expand on existing cash transfer schemes would be locally appropriate and could address the socioeconomic barriers to accessing and engaging with TB services faced by TB-affected households in Nepal. The findings have been used to inform the design of a socioeconomic support intervention for TB-affected households. The acceptability, feasibility and impact of this intervention on TB-related costs, stigma and TB treatment outcomes, is now being evaluated in a pilot implementation study in Nepal.
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Tuberculose , Humanos , Renda , Nepal , Pobreza , Pesquisa Qualitativa , Tuberculose/terapiaRESUMO
Precise positioning of neurons resulting from cell division and migration during development is critical for normal brain function. Disruption of neuronal migration can cause a myriad of neurological disorders. To investigate the functional consequences of defective neuronal positioning on circuit function, we studied a zebrafish frizzled3a (fzd3a) loss-of-function mutant off-limits (olt) where the facial branchiomotor (FBM) neurons fail to migrate out of their birthplace. A jaw movement assay, which measures the opening of the zebrafish jaw (gape), showed that the frequency of gape events, but not their amplitude, was decreased in olt mutants. Consistent with this, a larval feeding assay revealed decreased food intake in olt mutants, indicating that the FBM circuit in mutants generates defective functional outputs. We tested various mechanisms that could generate defective functional outputs in mutants. While fzd3a is ubiquitously expressed in neural and non-neural tissues, jaw cartilage and muscle developed normally in olt mutants, and muscle function also appeared to be unaffected. Although FBM neurons were mispositioned in olt mutants, axon pathfinding to jaw muscles was unaffected. Moreover, neuromuscular junctions established by FBM neurons on jaw muscles were similar between wildtype siblings and olt mutants. Interestingly, motor axons innervating the interhyoideus jaw muscle were frequently defasciculated in olt mutants. Furthermore, GCaMP imaging revealed that mutant FBM neurons were less active than their wildtype counterparts. These data show that aberrant positioning of FBM neurons in olt mutants is correlated with subtle defects in fasciculation and neuronal activity, potentially generating defective functional outputs.
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Neurônios Motores , Peixe-Zebra , Animais , Axônios , Movimento Celular , Neurogênese , Proteínas de Peixe-Zebra/genéticaRESUMO
This study compared the yield of tuberculosis (TB) active case finding (ACF) interventions applied under TB REACH funding. Between June 2017 to November 2018, Birat Nepal Medical Trust identified presumptive cases using simple verbal screening from three interventions: door-to-door screening of social contacts of known index cases, TB camps in remote areas, and screening for hospital out-patient department (OPD) attendees. Symptomatic individuals were then tested using smear microscopy or GeneXpert MTB/RIF as first diagnostic test. Yield rates were compared for each intervention and diagnostic method. We evaluated additional cases notified from ACF interventions by comparing case notifications of the intervention and control districts using standard TB REACH methodology. The project identified 1092 TB cases. The highest yield was obtained from OPD screening at hospitals (n = 566/1092; 52%). The proportion of positive tests using GeneXpert (5.5%, n = 859/15,637) was significantly higher than from microscopy testing 2% (n = 120/6309). (OR = 1.4; 95%CI = 1.12-1.72; p = 0.0026). The project achieved 29% additionality in case notifications in the intervention districts demonstrating that GeneXpert achieved substantially higher case-finding yields. Therefore, to increase national case notification for TB, Nepal should integrate OPD screening using GeneXpert testing in every district hospital and scale up of community-based ACF of TB patient contacts nationally.
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BACKGROUND: Treatment compliance is an important aspect for tuberculosis prevention and control. Poor compliance to treatment can lead to the development of drug-resistant tuberculosis. The aim of this study was to explore the factors affecting treatment compliance for tuberculosis patients. METHODS: Facility based unmatched case control study was done among the forty non-compliance and eighty compliance pulmonary tuberculosis patients registered at selected directly observed treatment short-course centers of six districts. Data were collected using in-depth interview guideline with the tuberculosis focal person and Focus Group Discussion with tuberculosis patients. RESULTS: A total of 120 respondents, 40 cases and 80 controls were enrolled in the study. About 72.5% of the cases and 56.2% of the controls were male. Five significant independent risk factors for non-compliance to TB treatment were identified. The qualitative session confirmed geographical barriers, inaccessibility to health facility, economic barriers, difficulty in convincing people, knowledge about Directly observed treatment shortcourse program, longer medication period, migration and stigma as a major barrier for treatment compliance. CONCLUSIONS: Wider ranges of barriers are prevalent in context of tuberculosis treatment pathway and outcome. Knowledge of the tuberculosis patients and attitude of the family plays a vital role in treatment compliance. Directly observed treatment shortcourse playing tremendous role to ensure treatment adherence has been identified as major barrier to adherence as well. Enablers of adherence need to be emphasized to address the barriers.