Learning from perpetrator replacement to remove crime opportunities and prevent poaching of the Sundarbans tiger.

Illegal wildlife trade (IWT) is one of the leading causes of the decline in high-value species. Crime-reduction strategies to counter IWT can have unintended effects, with crime displacement occurring when offenders react to such interventions. Despite the value of understanding how and why displacement occurs for informing conservation strategies, few examples are published. We explored a case of perpetrator replacement following an intervention and drew lessons for conservation strategies for high-value species. Poaching and subsequent trade threaten the Sundarbans tiger (Panthera tigris). Pirate gangs were the dominant poachers from 1980 to 2017, but following an extensive campaign, the Sundarbans was declared pirate free in 2018. We interviewed 280 individuals, including 100 tiger poachers, from 26 administrative unions bordering the Sundarbans and used interviewee responses to compare the poaching situation during and after the pirate era. We analyzed the spatial distribution of tiger poachers among the unions and used crime script analysis of the dominant poacher type to identify intervention. Because pirates opportunistically poached tigers, the government's successful counter-pirate campaign inadvertently removed the dominant tiger poaching type. However, a temporary reduction in poaching was rapidly cancelled out by the emergence of at least 32 specialist tiger-poaching teams. With the risk of extortion and robbery from pirates gone, other groups increased the frequency of opportunistic and targeted tiger poaching. Based on expert interviews, we estimated that 341 tiger poachers of all types are active throughout the unions, with 79% of specialists concentrated in 27% of unions. The highly focused counter-pirate campaign reduced motivations and opportunities for piracy but left intact the opportunity structure and trade connections for tiger poaching, and with insufficient enforcement officers trading has flourished. Interventions targeting opportunities for poaching by specialist tiger poachers include heightened surveillance and reporting mechanisms and alternative livelihood provision to disincentivize poaching.

Aprendizaje a partir de la sustitución del infractor para eliminar las oportunidades de crimen y prevenir la caza furtiva del tigre de Sundarbans Resumen El mercado ilegal de fauna (MIF) es una de las principales causas de la declinación de especies importantes. Las estrategias de reducción de crímenes para contrarrestar el MIF pueden tener efectos no deseados, como el desplazamiento del crimen que ocurre cuando los infractores reaccionan a dichas intervenciones. A pesar de lo valioso que es para las estrategias de conservación entender cómo y por qué ocurre este desplazamiento, se publican pocos ejemplos. Exploramos un caso de sustitución del infractor después de una intervención sacamos lecciones para las estrategias de conservación de especies importantes. La caza furtiva y el mercado subsecuente son una amenaza para el tigre de Sundarbans (Panthera tigris). Los piratas fueron los cazadores dominantes entre 1980 y 2017, pero después de una campaña exhaustiva, el Sundarbans fue declarado libre de piratas en 2018. Entrevistamos a 280 individuos, incluidos 100 cazadores furtivos, de 26 uniones administrativas que rodean al Sundarbans y usamos sus respuestas para comparar la situación de la caza furtiva durante y después de los piratas. Analizamos la distribución espacial de los cazadores furtivos entre las uniones y usamos el análisis de escritura criminal del tipo dominante de cazador para identificar las intervenciones. Ya que los piratas eran cazadores furtivos oportunistas, la campaña exitosa del gobierno para contrarrestarlos eliminó sin saberlo el tipo dominante de caza furtiva. Sin embargo, una reducción temporal de la caza se canceló rápidamente con la emergencia de al menos 32 equipos especialistas en la cacería furtiva de los tigres. Sin el riesgo de la extorsión o robo por parte de los piratas, otros grupos incrementaron la frecuencia de la cacería oportunista y focalizada. Con base en las entrevistas a expertos, estimamos que 341 cazadores de tigres de todos los tipos están activos en las uniones, con 79% de los especialistas concentrados en 27% de las uniones. La campaña focalizada anti-piratas redujo las motivaciones y oportunidades de piratería, pero no afectó la estructura de oportunidades y conexiones mercantiles de la cacería furtiva de tigres, lo cual, sumado a la falta de suficientes agentes policiales, ha aumentado el mercado. Las intervenciones enfocadas en las oportunidades de cacería de los cazadores especialistas incluyen una mayor vigilancia y mecanismos de reporte y el suministro de sustentos alternativos para desalentar la cacería furtiva.

Quality of life among health care workers with and without prior COVID-19 infection in Bangladesh.

BACKGROUND: Health care workers have been facing difficulties in coping with the COVID-19 infection from the beginning. The study aimed to compare Quality of Life (QOL) among health care workers (HCWs) with and without prior COVID-19 disease. METHODS: This study was conducted from July 2020 to January 2021 among 444 HCWs. We randomly interviewed 3244 participants for our earlier nationwide survey from a list of COVID-19 positive cases after their recovery, and we found 222 HCWs among the respondents. We randomly chose 222 HCWs unaffected by COVID as a comparison group from our selected hospitals. We measured QOL using World Health Organization's WHOQOL-BREF tool. Physical, psychological, environmental, and social ties were the four areas assessed on a 5-point Likert scale where a higher score suggests better QOL. Due to pandemic restrictions, we used telephonic interviews for data collection. RESULTS: A higher QOL score was observed in HCWs with prior COVID-19 infection in all four domains than HCWs without previous COVID-19 conditions. Comorbidity was negatively associated with QOL scores of the physical (p = 0.001) and (p < 0.001) and psychological (p = 0.05, and (p < 0.05) domains for non-COVID and COVID-affected groups, respectively. Current smoking was significantly associated with lower psychological (p = 0.019) and environmental (p = 0.007) QOL scores among HCWs with prior COVID-19 infection. Hospitalization history due to COVID infection was a contributing factor for lower physical QOL scores (p = 0.048). Environmental (p = 0.016) QOL scores were significantly associated with the monthly income in the prior COVID-19 infection group, and physical scores were significantly associated (p = 0.05) with a monthly income in the non-COVID group. CONCLUSION: Governmental and non-governmental stakeholders should focus on potentially modifiable factors to improve health care workers' quality of life.

Role of community-level emergency contraceptive pills awareness and possibilities of long-acting reversible or permanent methods in reducing unwanted births in Bangladesh: evidence from a nationwide cross-sectional survey.

OBJECTIVE: This study aims to investigate the role of community-level emergency contraceptive pill (ECP) awareness in reducing unwanted births (UWBs) in Bangladesh and explore the regional variation in women's appropriateness to adopt long-acting reversible contraceptives or permanent methods (LARCPMs) based on their child desire. DESIGN, SETTINGS AND PARTICIPANTS: We used data from the cross-sectional Bangladesh Demographic and Health Survey 2017-2018. We analysed the planning status of the last live birth 3 years preceding the survey of 20,127 ever-married women of reproductive age. METHODS: Considering women were nested within clusters, a mixed-effect multiple logistic regression was implemented to investigate the association between community-level ECP awareness and UWB by controlling for the effects of contextual, individual, and household characteristics. RESULTS: Only 3.7% of women belonged to communities with high ECP awareness. At the national level, 2% of women had UWB. About 2.1% of women who resided in communities of low ECP awareness had UWB, while UWB was only 0.5% among women residing in high ECP awareness communities. The odds of UWB was 71% lower among women who resided in high ECP awareness communities than among those who resided in communities with low ECP awareness. However, community-level ECP awareness could not avert mistimed birth. Dhaka, Chattogram and Rangpur held the highest share of UWB. Fertility persisted for 89% of the women who wanted no more children. Among women who wanted no more children, 15% were not using any method, 13% used traditional family planning methods and only 13% adopted LARCPM. These women mostly resided in Dhaka, followed by Chattogram and Rajshahi. CONCLUSION: This study highlights the significant positive role of ECP awareness in reducing UWB in Bangladesh. Findings may inform policies aimed at increasing LARCPM adoption, particularly among women residing in Dhaka and Chattogram who want no more children.

Assessment of COVID-19 management and its consequences on healthcare professionals: a cross-sectional study from Bangladesh.

OBJECTIVE: This explorative study aims to identify the gaps in COVID-19 management and their consequences on physicians in terms of contracting infection and psychological well-being during the early phase of the pandemic. DESIGN, SETTINGS AND PARTICIPANTS: We conducted a nationwide cross-sectional online study to collect information from 420 intern doctors who were at their internship in government medical colleges from February to August 2020. METHODS: We performed univariate and bivariate analyses to assess COVID-19 management. We investigated the consequences of COVID-19 management on infection risk, experiencing stress, developing anxiety, depression and sleep disturbance using five sets of multivariable logistic regression analyses. RESULTS: Findings indicate a delay in first-case detection and identify people's tendency to hide COVID-19 symptoms as one of the possible causes of that delay. About 56% of the intern doctors experienced that patients were trying to hide COVID-19 symptoms in the earlier phase of the pandemic. More than half of the respondents did not get any training on COVID-19 from their working institutions. About 30% and 20% of the respondents did not use personal protective equipment (PPE) and masks while treating patients. Respondents who treated patients without PPE, masks, face shields and gloves were almost two times as likely to be infected by COVID-19. The odds of experiencing COVID-19-related stress was almost twofold among respondents who treated patients without wearing PPE and masks. Experiencing COVID-19-related stress was further associated with an increased risk of developing anxiety and depression that led to sleep disturbance. CONCLUSION: Ensuring the maximum utilization of limited resources during any public health crisis such as COVID-19 needs developing coping mechanisms by projecting future demand. Ensuring proper training and safety measures can reduce physical and psychological hazards among physicians.

Lockdowns, Community Mobility Patterns, and COVID-19: A Retrospective Analysis of Data from 16 Countries.

OBJECTIVES: During the coronavirus disease 2019 (COVID-19) pandemic, countries around the world framed specific laws and imposed varying degrees of lockdowns to ensure the maintenance of physical distancing. Understanding changes in temporal and spatial mobility patterns may provide insights into the dynamics of this infectious disease. Therefore, we assessed the efficacy of lockdown measures in 16 countries worldwide by analyzing the relationship between community mobility patterns and the doubling time of COVID-19. METHODS: We performed a retrospective record-based analysis of population-level data on the doubling time for COVID-19 and community mobility. The doubling time for COVID-19 was calculated based on the laboratory-confirmed cases reported daily over the study period (from February 15 to May 2, 2020). Principal component analysis (PCA) of six mobility pattern-related variables was conducted. To explain the magnitude of the effect of mobility on the doubling time, a finite linear distributed lag model was fitted. The k-means clustering approach was employed to identify countries with similar patterns in the significant co-efficient of the mobility index, with the optimal number of clusters derived using Elbow's method. RESULTS: The countries analyzed had reduced mobility in commercial and social places. Reduced mobility had a significant and favorable association with the doubling time of COVID-19-specifically, the greater the mobility reduction, the longer the time taken for the COVID-19 cases to double. CONCLUSIONS: COVID-19 lockdowns achieved the immediate objective of mobility reduction in countries with a high burden of cases.

A multilevel assessment of the influence of education on women's uptake of institutional delivery services during childbirth in Bangladesh.

OBJECTIVES: Despite a significant decline over time, maternal mortality remains high in Bangladesh. Institutional delivery during childbirth is crucial to reducing maternal mortality, but uptake of institutional delivery services (IDS) remains suboptimal in Bangladesh. Though women's education plays a crucial role in the use of IDS, the educational status of the household head and area-level literacy rate also appear to act as predictors of IDS uptake. This study aims to assess the effect of the educational status of women and household heads as well as district-level adult literacy rates on the use of IDS during childbirth among women in Bangladesh. DESIGN: This study analyzed nationally representative cross-sectional survey data from the 2019 Bangladesh Multiple Indicator Cluster Survey. SETTING: Bangladesh. PARTICIPANTS: 9,207 currently married women aged 15-49 years who had at least one live birth in the two years preceding the survey were included in the study. The outcome measure was women's use of IDS during their last childbirth. A multilevel logistic regression model was used to explore the association between education status of women and household heads, and district (i.e., area unit) adult literacy rates and uptake of IDS among women in Bangladesh by controlling for other sociodemographic covariates and clustering. RESULTS: About 53% of women used IDS during childbirth. Adjusting for other factors and clustering, women with higher educational status, those living in households with higher-educated heads, and those in districts with greater adult literacy rates are more likely to use IDS, after controlling for key sociodemographic variables including wealth. CONCLUSIONS: Uptake of IDS in Bangladesh remains low, with education playing an important independent role in determining rates. The findings of the study provide empirical evidence for policymakers to design multi-modal educational programs targeted not only at literate women but also at household head (especially male) and communities where literacy (and equally importantly health literacy) may be variable or absent.

Rural-urban differentials in the influences of individual and geospatial preparedness on institutional childbirth: a cross-sectional study in Bangladesh.

OBJECTIVE: This study aims to explore the rural-urban differentials in the influences of individual and geospatial preparedness on institutional childbirth in Bangladesh. A related aim of this paper is to derive estimates to measure geospatial preparedness for institutional births, through statistical modelling, when no data are available for measuring this areal indicator. DESIGN, SETTINGS AND PARTICIPANTS: The paper used data from a large-scale nationally representative Bangladesh Multiple Indicator Cluster Survey 2019. The analytical sample included 9203 currently married women of reproductive age who had a live birth in the 2 years preceding the survey. METHODS: Mixed effect logistic regression models were employed to explore the rural-urban differentials in influences of individual and geospatial preparedness on institutional childbirth. The district-level random effect estimation was done to measure geospatial preparedness. The conditional autoregressive model was used to examine the association of geospatial preparedness with areal variation in institutional births. RESULTS: In rural settings, women who gave birth to a female newborn were 18% less likely to have facility births compared with women who gave birth to a male newborn. Also, women from households in the highest wealth quintile were twice as likely to have facility births compared with those from households in the poorest wealth quintile. In contrast, in urban areas, facility births did not vary by sex of the fetus or by households' socioeconomic status. The geospatial preparedness explained 8% and 9% of the variability in institutional births in rural and urban areas, respectively. Geospatial mapping revealed low preparedness in the hill tracts. Findings identified geospatial preparedness as a potential source of areal variation in facility births. CONCLUSION: Findings suggest improving district-level preparedness and developing differential programme strategies for urban and rural areas to increase the national prevalence and more equitable use of institutional childbirth in Bangladesh.

Health-related quality of life and coping strategies adopted by COVID-19 survivors: A nationwide cross-sectional study in Bangladesh.

INTRODUCTION: This study aims to investigate the health-related quality of life and coping strategies among COVID-19 survivors in Bangladesh. METHODS: This is a cross-sectional study of 2198 adult, COVID-19 survivors living in Bangladesh. Data were collected from previously diagnosed COVID-19 participants (confirmed by an RT-PCR test) via door-to-door interviews in the eight different divisions in Bangladesh. For data collection, Bengali-translated Brief COPE inventory and WHO Brief Quality of Life (WHO-QoLBREF) questionnaires were used. The data collection period was from October 2020 to March 2021. RESULTS: Males 72.38% (1591) were more affected by COVID-19 than females 27.62% (607). Age showed significant correlations (p<0.005) with physical, psychological and social relationships, whereas gender showed only a significant correlation with physical health (p<0.001). Marital status, occupation, living area, and co-morbidities showed significant co-relation with all four domains of QoL (p<0.001). Education and affected family members showed significant correlation with physical and social relationship (p<0.001). However, smoking habit showed a significant correlation with both social relationship and environment (p<0.001). Age and marital status showed a significant correlation with avoidant coping strategies (p<0.001); whereas gender and co-morbidities showed a significant correlation with problem-focused coping strategies (p<0.001). Educational qualification, occupation and living area showed significant correlation with all three coping strategies(p<0.001). CONCLUSION: Survivors of COVID-19 showed mixed types of coping strategies; however, the predominant coping strategy was avoidant coping, followed by problem-focused coping, with emotion-focused coping reported as the least prevalent. Marital status, occupation, living area and co-morbidities showed a greater effect on QoL in all participants. This study represents the real scenario of nationwide health-associated quality of life and coping strategies during and beyond the Delta pandemic.

COVID-19 vaccine acceptance in South Asia: a multi-country study.

OBJECTIVES: With COVID-19 vaccination underway, this study aimed to understand belief, attitude and intention of the people in the South Asia region towards the vaccine. METHODS: We conducted a cross-sectional study using semi-structured questionnaires among 18201 individuals in four South Asian countries; Bangladesh, India, Pakistan, and Nepal between January 17 and February 2, 2021. We used the Health Belief Model (HBM) to identify the predictors related to vaccine acceptance. STATA (v16.1) was used for all analyses. RESULTS: The percentage of respondents willing to be vaccinated against COVID-19 was 65%, 66%, 72% and 74% for Bangladesh, India, Pakistan and Nepal, respectively. Perceived destructive impact of COVID-19, positive perception of vaccines and concern about possible side effects were significant in modifying respondents' intentions.. In multivariable logistic regression, age, sex, marital status, education, comorbidities, worry about getting infected, perceived COVID-19 impact, belief regarding vaccine efficacy, positive attitude towards mandatory measures, and vaccine availability were found to be associated with vaccine acceptance across countries. CONCLUSION: Nearabout two-third of the respondants were willing to take COVID-19 vaccine in the four South Asia countries.

A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study.

BACKGROUND: Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. PROCEDURE: Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m(2)/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated. RESULTS: Twenty-one patients, median age 7.5 (range 0.8-25.6) years were treated with 2 mg/m(2) (n = 4), 3 mg/m(2) (n = 3), or 4 mg/m(2) (n = 14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1-18) courses was given. Two dose limiting toxicities (grade 3 hypophosphatemia) occurred at 4 mg/m(2) zoledronic acid. Other grades 3-4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 1), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3-18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL-6 levels decreased with therapy. CONCLUSIONS: Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m(2) every 28 days.

Revisit the correlates of infant mortality in Bangladesh: findings from two nationwide cross-sectional studies.

OBJECTIVE: The main objective of this study is to investigate how the direction and strength of the association between infant mortality and its predictors are changing over time in Bangladesh using a nationally representative sample for the period 2011-2014. DESIGN, SETTING AND PARTICIPANTS: Data from two repeatedly cross-sectional Bangladesh Demographic and Health Surveys (BDHSs) for the years 2011 and 2014 were used. A total of 7664 (with 312 infant death) and 7048 (with 264 infant death) complete cases, respectively, from BDHS 2011 and 2014 datasets were included in the study. METHODS: Cox's proportional hazard model with robust standard error (SE) that adjusts for the complex survey design characteristics was implemented to assess how the risk factors associated with infant mortality change their paths. RESULTS: Results reflected that administrative division remained as a potential risk factor of infant death for both periods. Household's socioeconomic status, father's employment status, age difference between parents turned out to be potential risk factors in 2014, though they did not show any significant association with infant death in the year 2011. In contrast to 2011, mothers' individual-level characteristics such as age at childbirth, education, media exposure, employment status did not remain as significant risk factors for infant death in 2014. Younger fathers increased the burden of death among infants of adolescent mothers. At higher order births, the burden of infant death significantly shifted from rural to urban areas. From the year 2011 to 2014, urban areas achieved socioeconomic equity in infant survival, while the extent of inequity was increased in rural areas. CONCLUSION: Community-based programmes should be designed for urban mothers who are expecting higher order births. To eradicate the socioeconomic inequity in infant survival, the government should design strong and sustainable maternal and child healthcare facilities, especially for rural areas.

Quality of life of COVID-19 recovered patients in Bangladesh.

Coronavirus Disease-2019 (COVID-19) quickly surged the whole world and affected people's physical, mental, and social health thereby upsetting their quality of life. Therefore, we aimed to investigate the quality of life (QoL) of COVID-19 positive patients after recovery in Bangladesh. This was a study of adult (aged ≥18 years) COVID-19 individuals from eight divisions of Bangladesh diagnosed and confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) from June 2020 to November 2020. Given a response rate of 60% in a pilot study, a random list of 6400 COVID-19 patients was generated to recruit approximately 3200 patients from eight divisions of Bangladesh and finally a total of 3244 participants could be recruited for the current study. The validated Bangla version of the World Health Organization Quality of Life Brief (WHOQOL-BREF) questionnaire was used to assess the QoL. Data were analyzed by STATA (Version 16.1) and R (Version 4.0.0). All the procedures were conducted following ethical approval and in accordance with the Declaration of Helsinki. The mean scores of QoL were highest for the physical domain (68.25±14.45) followed by social (65.10±15.78), psychological (63.28±15.48), and environmental domain (62.77±13.07). Psychological and physical domain scores among females were significantly lower than the males (p<0.001). The overall quality of life was lower in persons having a chronic disease. Participants over 45 years of age were 52% less likely to enjoy good physical health than the participants aged below 26 years (AOR: 0.48, CI: 0.28-0.82). The quality of life of employed participants was found 1.8 times higher than the unemployed (AOR: 1.80, CI: 1.11-2.91). Those who were admitted to hospitals during infection had a low QoL score in physical, psychological, and socials domains. However, QoL improved in all aspect except the psychological domain for each day passed after the diagnosis. These findings call for a focus on the quality of life of the COVID-19 affected population, with special emphasis given to females, older adults, unemployed, and people with comorbidities.

Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma.

Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.

Identifying the Associated Risk Factors of Sleep Disturbance During the COVID-19 Lockdown in Bangladesh: A Web-Based Survey.

BACKGROUND: Bangladesh, a developing country with a lower-middle-income and one of the world's most densely populated areas, has been severely affected by COVID-19. This global epidemic is not only affecting the physical health of the patients but also causing severe psychological effects among those who have not yet been infected. Sleep disturbance is one of the key symptoms of major depression and one of the proven risk factors for suicide. The objective of this study is to identify the risk factors associated with sleep disturbance which has developed as a general impact of COVID-19 and new normal life during the lockdown (a measure to control the spread of COVID-19) in Bangladesh. METHODS: Demographic characteristics, COVID-19, and lockdown related information have been collected from 1,128 individuals by conducting a web-based survey. Respondent's perspective regarding sleep disturbance during COVID-19 lockdown is considered as the outcome of interest which is dichotomous. Descriptive statistics methods have been applied to explore the distribution of respondent's demographic characteristics. Pearson's chi-square tests have been performed to relate the sleep disturbance status of the respondents to their demographic, personal, and COVID-19 related information. Furthermore, a multivariable logistic regression model has been adopted to identify the significant association of sleep disturbance with the demographic, COVID-19, and lockdown related information of respondents during the COVID-19 lockdown in Bangladesh. FINDINGS: The prevalence of sleep disturbance during the COVID-19 lockdown is found to be higher among participants aged 31-40 years. Gender disparity has also been observed in favor of male participants, whereas no significant regional heterogeneity has been found. Working from home or doing online classes during the lockdown has been found as a potential predictive factor of sleep disturbance. Losing a job has been considered as an adverse economic effect of COVID-19, which also induces sleep disturbance. Perception regarding the risk of getting infected and anxiety triggered the chance of developing sleep disturbance. The sleeping schedule is also found as a risk factor for sleep disturbance. CONCLUSION: Evidence-based policies are required to combat psychological challenges that have arisen due to COVID-19, primarily targeting the groups who are largely suffering from sleep disturbance.

Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma.

Drug resistance is a major cause of treatment failure in cancer. Here, we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin (IL)-6 alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also regulatory T cells (Treg) and nonmyeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.

Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis.

Neuroblastoma is the most common extracranial solid tumor in the pediatric population. Sorafenib (Nexavar), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in certain types of cancers. Here, we tested antitumor effects of sorafenib (≤ 10 µM) on four human neuroblastoma cell lines, CHLA255, CHLA171, CHLA90 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis of neuroblastoma tumor cells in a dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 and sphingosine-1-phosphate (S1P), a recently identified regulator for STAT3, in these tumor cells. Moreover, sorafenib downregulated phosphorylation of MAPK (p44/42) in neuroblastoma cells, consistent with inhibition of their upstream regulators MEK1/2. Sorafenib inhibited expression of cyclin E, cyclin D1/D2/D3, key regulators for cell cycle, and the antiapoptotic proteins Mcl-1 and survivin. Finally, sorafenib suppressed the growth of human neuroblastoma cells in a mouse xenograft model. Taken together, these findings suggest the potential use of sorafenib for the treatment of pediatric neuroblastomas.

Interleukin-6 in bone metastasis and cancer progression.

The bone and bone marrow are among the most frequent sites of cancer metastasis. It is estimated that 350,000 patients die with bone metastases annually in the United States. The ability of tumor cells to colonize the bone marrow and invade the bone is the result of close interactions between tumor cells and the bone marrow microenvironment. In this article, we review the contribution of interleukin-6 (IL-6) produced in the bone marrow microenvironment to bone metastasis. This cytokine has a strong pro-tumorigenic activity due to its multiple effects on bone metabolism, tumor cell proliferation and survival, angiogenesis, and inflammation. These effects are mediated by several signaling pathways, in particular the Janus kinase/signal transducer and transcription activator (JAK/STAT-3), Ras/mitogen activated protein kinase (MAPK), and phosphoinositol-3 kinase (PI3K)-protein kinase B/Akt (PkB/Akt), which are activated by IL-6 and amplified in the presence of soluble IL-6 receptor (sIL-6R). Supporting the role of IL-6 in human cancer is the observation of elevated serum levels of IL-6 and sIL-6R in patients with bone metastasis and their association with a poor clinical outcome. Over the last decade several large (monoclonal antibodies) and small (inhibitors of IL-6 mediated signaling) molecules that inhibit IL-6 activity in preclinical models have been developed. Several of these inhibitors are now undergoing phases I and II clinical trials, which will determine their inclusion in the list of effective targeted agents in the fight against cancer.

Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells.

Neuroblastoma, the second most common solid tumor in children, frequently metastasizes to the bone marrow and the bone. Neuroblastoma cells present in the bone marrow stimulate the expression of interleukin-6 (IL-6) by bone marrow stromal cells (BMSC) to activate osteoclasts. Here we have examined whether stromal-derived IL-6 also has a paracrine effect on neuroblastoma cells. An analysis of the expression of IL-6 and its receptor, IL-6R, in 11 neuroblastoma cell lines indicated the expression of IL-6 in 4 cell lines and of IL-6R in 9 cell lines. Treatment of IL-6R-positive cells with recombinant human IL-6 resulted in signal transducer and activator of transcription-3 and extracellular signal-regulated kinase-1/2 activation. Culturing IL-6R-positive neuroblastoma cells in the presence of BMSC or recombinant human IL-6 increased proliferation and protected tumor cells from etoposide-induced apoptosis, whereas it had no effect on IL-6R-negative tumor cells. In vivo, neuroblastoma tumors grew faster in the presence of a paracrine source of IL-6. IL-6 induced the expression of cyclooxygenase-2 in neuroblastoma cells with concomitant release of prostaglandin-E2, which increased the expression of IL-6 by BMSC. Supporting a role for stromal-derived IL-6 in patients with neuroblastoma bone metastasis, we observed elevated levels of IL-6 in the serum and bone marrow of 16 patients with neuroblastoma bone metastasis and in BMSC derived from these patients. Altogether, the data indicate that stromal-derived IL-6 contributes to the formation of a bone marrow microenvironment favorable to the progression of metastatic neuroblastoma.

Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages.

Tumor infiltration with Valpha24-invariant NKT cells (NKTs) associates with favorable outcome in neuroblastoma and other cancers. Although NKTs can be directly cytotoxic against CD1d+ cells, the majority of human tumors are CD1d-. Therefore, the role of NKTs in cancer remains largely unknown. Here, we demonstrate that CD68+ tumor-associated monocytes/macrophages (TAMs) represented the majority of CD1d-expressing cells in primary human neuroblastomas. TAMs stimulated neuroblastoma growth in human cell lines and their xenografts in NOD/SCID mice via IL-6 production. Indeed, TAMs produced IL-6 in primary tumors and in the BM of patients with metastatic neuroblastoma. Gene expression analysis using TaqMan low-density arrays of 129 primary human neuroblastomas without MYCN amplification revealed that high-level expression of TAM-specific genes (CD14, CD16, IL6, IL6R, and TGFB1) was associated with poor 5-year event-free survival. While NKTs were not cytotoxic against neuroblastoma cells, they effectively killed monocytes pulsed with tumor cell lysate. The killing of monocytes was CD1d restricted because it was inhibited by a CD1d-specific mAb. Cotransfer of human monocytes and NKTs to tumor-bearing NOD/SCID mice decreased monocyte number at the tumor site and suppressed tumor growth compared with mice transferred with monocytes alone. Thus, killing of TAMs reveals what we believe to be a novel mechanism of NKT antitumor activity that relates to the disease outcome.

Mechanisms of invasion and metastasis in human neuroblastoma.

Neuroblastoma is the second most common solid tumor in children that is metastatic in 70% of patients at the time of diagnosis. The ability of neuroblastoma cells to colonize distant organs like the bone marrow and the bone is the result of close interactions between tumor cells and the microenvironment. Significant progress has been recently made in our understanding of the mechanisms that promote the colonization and invasion of the bone by neuroblastoma cells and these mechanisms are reviewed in this article. How this understanding is now allowing us to test new therapeutic agents specifically targeted at interfering with neuroblastoma metastasis is then discussed.