COVID-19 Vaccine Hesitancy among Population in Jazan Region of Saudi Arabia.

COVID-19 vaccine acceptance and refusal vary across countries and among different socio-demographic groups. This study investigates hesitancy related to the COVID-19 vaccine and the associated factors in the rural-community-dominated Jazan Province, Saudi Arabia. A cross-sectional study through an online questionnaire was conducted from February to April 2021 to investigate the extent of vaccine hesitancy related to the COVID-19 vaccine and the associated factors in the Jazan region. A Chi-squared test and post hoc analysis were conducted to analyze the statistical significance of the association between variables. Of the 569 participants who completed the online questionnaire, the majority were males (81.5%) and had a university education (72.6%). Of the participants, more than one-third (36.9%) were hesitant to vaccinate. Concern about adverse side effects following vaccination was the most reported reason for vaccine hesitancy (42.6%), followed by beliefs that the vaccine was unsafe or ineffective (15.5%). The data analysis revealed that people who lived in cities in Jazan Province or those who did not have a family history of COVID-19 infection were more likely to be vaccine hesitant. It is more important than ever to develop and implement community-based strategies to address vaccine hesitancy, especially in rural areas.

In response to the Saudi healthcare reform: a cross-sectional study of awareness of and attitudes toward the public health model among health students.

Background: Saudi Arabia's health sector is experiencing a significant transformation toward an emphasis on the public health model. This model is a population-based approach to preventing and controlling disease, and its importance becomes evident during infectious outbreaks and pandemics, such as COVID-19. This study aimed to assess the awareness and attitudes of health students in Jazan toward the public health model. Methods: This study applied a cross-sectional online survey. Data were collected from 3-18 November 2020 using Google Forms. A convenience sampling method was used with a final sample of 425 participants. Results: Most participants (71%) were aware of the public health model, with an average score of 11.36 out of 16. Multiple regression analysis revealed a significant association between the awareness level of the public health model and participants' demographics, namely, gender, major of study, year of study, and prior training in public health. Participants who completed public health training (ß = 0.220) had higher awareness scores than others. On the other hand, participants from public health (ß = -0.342), medicine (ß = 0.164), and nursing in Jazan (ß = 0.128) had higher awareness of the public health model than the reference group (Nursing at Addayer College). Addayer is an area located in the rural northeast of the Jazan region. In addition, final-year students (ß = 0.113) had higher awareness of the public health model than the reference group (year 2 pre-final students). Female participants (ß = -0.142) had lower awareness of the public health model than male participants. Most participants (95.3%) believed that the clinical care and public health models are essential for promoting people's health. However, 4.7% of participants believed that clinical health care is more important than public health. Conclusion: Health students, who are future healthcare professionals, must understand and value the public health model to support the planned health system reforms. It is recommended to evaluate how the education and training of students in public health, medicine, and nursing in Jazan impact the understanding and views of this cohort on the public health model compared to those of students in other health-related majors.

Low Serum Hepcidin Levels in Patients with Ulcerative Colitis - Implications for Treatment of Co-existent Iron-Deficiency Anemia.

Ulcerative colitis (UC) is often associated with anemia. Hepcidin, the central regulator of iron homeostasis, is known to be induced by inflammation and suppressed by anemia. It is not clear how hepcidin is affected in those with UC, when both inflammation and anemia may co-exist.Such knowledge may hold implications for treatment. Hematological and iron-related parameters, C-reactive protein (CRP), growth differentiation factor 15 (GDF-15) and erythroferrone (ERFE) (erythroid regulators of hepcidin) levels were estimated in blood from those with UC and in control subjects. Values for hematological and iron-related parameters showed evidence of iron-deficiency and resultant anemia, in patients with UC. The presence of UC was significantly associated with inflammation. Serum levels of ERFE, but not of GDF-15, were significantly higher in patients with UC than in control patients, while hepcidin levels were significantly lower. Serum hepcidin concentrations in patients with UC correlated positively with serum iron, ferritin and GDF-15, and negatively with serum ERFE. The iron status and serum hepcidin levels in UC patients with co-existent anemia were significantly lower and serum ERFE values significantly higher than in those with UC without anemia. The effect of anemia on hepcidin predominated over that of inflammation in patients with UC, resulting in suppressed hepcidin levels. This effect is possibly mediated through erythroferrone. We suggest that a serum hepcidin-guided approach may be useful to guide use of oral iron supplements to treat co-existent iron-deficiency anemia in patients with UC and other chronic inflammatory diseases.

Impaired pancreatic beta-cell function after a single dose of oral iron: A before-and-after (pre-post) study.

BACKGROUND: Although in vitro and animal studies have shown that iron loading in pancreatic beta cells impairs insulin secretion, no human studies have documented the acute effects of oral iron on beta-cell insulin secretory capacity. In the present study, we determined beta-cell insulin secretory capacity at baseline and after a single oral dose of iron (ferrous sulphate, 120 mg elemental iron) in healthy male individuals. METHODS: Fifteen healthy male volunteers underwent an oral glucose tolerance test (OGTT) to document baseline glucose tolerance and insulin secretion kinetics (baseline OGTT). One week later, the same subjects underwent a second OGTT, 2 h after an oral dose of ferrous sulphate (120 mg of elemental iron) (post-iron OGTT). Changes in disposition index, insulin secretion kinetics, glucose tolerance, insulin resistance, insulin clearance and iron-related parameters in serum were determined. RESULTS: Compared to baseline OGTT, the areas under the curve (AUC) for serum iron and transferrin saturation increased by 125% and 118%, respectively, in the post-iron OGTT. The disposition index decreased by 20% (p = 0.009) and the AUC for glucose concentrations increased by 5.7% (p < 0.001) during the post-iron OGTT. The insulin secretion rate was marginally lower during the first hour (-3.5%, p = 0.63), but became significantly higher during the second hour (22%, p = 0.005) of the post-iron OGTT. Insulin resistance and insulin clearance rate were not affected by iron intake. CONCLUSIONS: The decrease in disposition index and glucose tolerance observed after the oral dose of iron points to an acute iron-induced impairment in pancreatic beta-cell insulin secretory capacity.

Insulin resistance and adipose tissue inflammation induced by a high-fat diet are attenuated in the absence of hepcidin.

Increased body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying basis of these associations is unclear. To attempt to investigate this, we studied the development of IR and associated inflammation in adipose tissue in the presence of increased body iron stores. Male hepcidin knock-out (Hamp1-/-) mice, which have increased body iron stores, and wild-type (WT) mice were fed a high-fat diet (HFD) for 12 and 24 weeks. Development of IR and metabolic parameters linked to this, insulin signaling in various tissues, and inflammation and iron-related parameters in visceral adipose tissue were studied in these animals. HFD-feeding resulted in impaired glucose tolerance in both genotypes of mice. In response to the HFD for 24 weeks, Hamp1-/- mice gained less body weight and developed less systemic IR than corresponding WT mice. This was associated with less lipid accumulation in the liver and decreased inflammation and lipolysis in the adipose tissue in the knock-out mice, than in the WT animals. Fewer macrophages infiltrated the adipose tissue in the knockout mice than in wild-type mice, with these macrophages exhibiting a predominantly anti-inflammatory (M2-like) phenotype and indirect evidence of a possible lowered intracellular iron content. The absence of hepcidin was thus associated with attenuated inflammation in the adipose tissue and increased whole-body insulin sensitivity, suggesting a role for it in these processes.

Gift authorship: Look the gift horse in the mouth.

Unmerited authorship in research papers is widely acknowledged to constitute research misconduct. In different contexts, it has been called "gift", "honorary", or "guest" authorship. Although several attempts have been made to address the issue, it remains a significant problem in research. In this paper, we discuss accepted criteria that qualify a person to be an author on a research publication and define what constitutes "gift authorship". We also look at the scenario in India and try to identify the circumstances that have fostered this practice in academia in the country. Finally, we discuss the adverse effects of this practice on the research enterprise as a whole, and possible remedial measures.

Examining the Correlation of Google Influenza Trend with Hospital Data: Retrospective Study.

INTRODUCTION: Many studies have explored social media and users search activities such as Google Trends to predict and detect influenza activities. Studies that examined Google Trends correlation with the actual hospital influenza cases were conducted in non-tropical regions that have clearly defined seasons. Tropical areas are known for having less-defined seasonality and the extent of Google Trends concordance with actual influenza cases is unknown for these areas. The goal of this study is to compare Google Trends with hospital cases in tropical regions. METHODS: We analyzed 48,263 influenza cases in the time period of 2010 to 2019. The cases were retrieved from central hospital medical records in tropical regions using the corresponding codes for influenza ICD-10 AM. Cases from the medical records were compared with Google Trends to determine trends, seasonality, and correlation. RESULTS: Graphically, there were some similar areas of the trend, but cross-correlation analysis did not show any significant correlation between hospital and Google Trends with a maximum correlation rate of 0.300. Seasonality analysis showed a clear pattern that peaked around November in Google Trends while hospital data showed less defined seasonality with a smaller peak occurring at the end of December and beginning of January. CONCLUSION: Based on the results, there is a weak correlation between Google Trends and hospital data. More innovative methods are emerging to predict influenza activity using social media and user search data and further study is needed to examine the concurrent trends derived using these methods across regions that have different humidity levels and temperatures.

Evidence of dysregulated iron homeostasis in newly diagnosed diabetics, but not in pre-diabetics.

AIM: Diabetes mellitus has been reported to be associated with increased serum levels of ferritin. The basis of this association is unclear. It is also not precisely known whether other iron-related parameters, including hepcidin (the central regulator of systemic iron homeostasis), are affected under these circumstances. This study attempted to determine this. METHODS: Adult men (normoglycemic or newly diagnosed with diabetes or pre-diabetes) were recruited. Anthropometric, metabolic, and hematological and iron-related parameters in blood were measured. Indices of insulin resistance (HOMA-IR) and pancreatic beta cell function (HOMA-ß) were calculated. RESULTS: Subjects in the 3 groups were similar in age, and anthropometric and hematological parameters. Serum ferritin and hepcidin levels were higher in diabetics, than in pre-diabetics and in control subjects. These elevations seen were not linked to the presence of inflammation. HOMA-IR was higher in diabetics, and HOMA-ß lower in diabetics and pre-diabetics, than in control subjects. HOMA-IR and serum ferritin were positively correlated with one another. CONCLUSION: Elevated levels of serum ferritin and hepcidin in newly diagnosed diabetics (but not pre-diabetics) indicate dysregulated iron homeostasis, with the former positively associated with insulin resistance in these patients.

Experiences of a new cadre of midwives in Bangladesh: findings from a mixed method study.

BACKGROUND: Bangladesh did not have dedicated professional midwives in public sector health facilities until recently, when the country started a nation-wide programme to educate and deploy diploma midwives. The objective of the findings presented in this paper, which is part of a larger study, was to better understand the experience of the midwives of their education programme and first posting as a qualified midwife and to assess their midwifery knowledge and skills. METHODS: We applied a mixed method approach, which included interviewing 329 midwives and conducting 6 focus group discussions with 43 midwives and midwifery students. Sampling weights were used to generate representative statistics for the entire cohort of the midwives deployed in the public sector health facilities. RESULTS: Most of the midwives were satisfied with different dimensions of their education programme, with the exception of the level of exposure they had to the rural communities during their programme. Out of 329 midwives, 50% received tuition fee waivers, while 46% received funding for educational materials and 40% received free accommodation. The satisfaction with the various aspects of the current posting was high and nearly all midwives reported that a desire to work in the public sector in the long run. However, a significant proportion of the midwives expressed concerns with equipment, accommodation, transport and prospect of transfers. The scores on the knowledge test and self-reported skill levels were varied but reasonably high. CONCLUSION: While the midwives are highly motivated, satisfied with many aspects of their current jobs and have adequate knowledge and skills, there are some bottlenecks and concerns that, if unaddressed, may derail the success of this programme. To capture the career progress of these midwives, additional research, including a follow-up study with the same cohort of midwives, would be beneficial to this programme.

Development of insulin resistance preceded major changes in iron homeostasis in mice fed a high-fat diet.

Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) have been associated with dysregulation of iron metabolism. The basis for this association is not completely understood. To attempt to investigate this, we studied temporal associations between onset of insulin resistance (IR) and dysregulated iron homeostasis, in a mouse model of T2DM. Male C57Bl/6 mice (aged 8 weeks) were fed a high-fat diet (HFD; 60% energy from fat) or a control diet (CD; 10% energy from fat) for 4, 8, 12, 16, 20 and 24 weeks. Development of IR was documented, and various metabolic, inflammatory and iron-related parameters were studied in these mice. HFD-feeding induced weight gain, hepato-steatosis and IR in the mice. Onset of IR occurred from 12 weeks onwards. Hepatic iron stores progressively declined from 16 weeks onwards. Accompanying changes included a decrease in hepatic hepcidin (Hamp1) mRNA expression and serum hepcidin levels and an increase in iron content in the epididymal white adipose tissue (eWAT). Iron content in the liver negatively correlated with that in the eWAT. Factors known to regulate hepatic Hamp1 expression (such as serum iron levels, systemic inflammation, and bone marrow-derived erythroid regulators) were not affected by HFD-feeding. In conclusion, the results show that the onset of IR in HFD-fed mice preceded dysregulation of iron homeostasis, evidence of which were found both in the liver and visceral adipose tissue.

Iron homeostasis is dysregulated, but the iron-hepcidin axis is functional, in chronic liver disease.

BACKGROUND: Perturbations in iron homeostasis have been reported to be associated with irreversible liver injury in chronic liver disease (CLD). However, it is not clear whether liver dysfunction per se underlies such dysregulation or whether other factors also contribute to it. This study attempted to examine the issues involved. METHODS: Patients diagnosed to have chronic liver disease (n = 63), who underwent a medically-indicated upper gastrointestinal endoscopy, were the subjects of this study. Patients with dyspepsia, who underwent such a procedure, and were found to have no endoscopic abnormalities, were used as control subjects (n = 49). Duodenal mucosal samples were obtained to study mRNA and protein levels of duodenal proteins involved in iron absorption. A blood sample was also obtained for estimation of hematological, iron-related, inflammatory and liver function-related parameters. RESULTS: Patients with CLD had impaired liver function, anemia of inflammation and lower serum levels of hepcidin than control subjects. Gene (mRNA) expression levels of duodenal ferroportin and duodenal cytochrome b (proteins involved in iron absorption) were decreased, while that of divalent metal transporter-1 (DMT-1) was unchanged. Protein expression of DMT-1 was, however, decreased while that of ferroportin was unchanged. In the CLD group, serum hepcidin was predicted independently by serum ferritin and hemoglobin, but not by C-reactive protein (a marker of inflammation). CLD patients with serum ferritin greater than 300 µg/dL had significantly greater liver dysfunction (as indicated by significantly higher serum concentrations of bilirubin, AST and ALT, and MELD scores), higher serum concentrations of CRP and hepcidin, and higher ferroportin protein expression, than those with serum ferritin ≤ 300 µg/dL. CONCLUSIONS: In patients with CLD, anemia of inflammation and low serum hepcidin levels were found to paradoxically co-exist. Expression of duodenal proteins involved in iron absorption were either decreased or unaltered in these patients. The hepcidin response to higher body iron levels and/or inflammation appeared to be functional in these patients, despite the presence of liver disease.

Enhanced insulin signaling and its downstream effects in iron-overloaded primary hepatocytes from hepcidin knock-out mice.

BACKGROUND: Increased body iron stores have been implicated in the pathogenesis of diabetes mellitus. However, the molecular mechanisms involved are unclear. The liver plays a central role in homeostasis of iron and glucose in the body. Mice deficient in hepcidin (the central regulator of systemic iron homeostasis) (Hamp1-/- mice) accumulate iron in the liver in vivo. The effects of such iron loading on hepatic insulin signaling and glucose metabolism are not known. METHODS: Hepatocytes isolated from Hamp1-/- mice were studied for markers of insulin signaling (and its downstream effects), glucose production, expression of gluconeogenic and lipogenic enzymes, and markers of AMPK (AMP-activated protein kinase) activation and oxidative stress. These parameters were studied both in the absence and presence of insulin, and also with the use of an iron chelator. RESULTS: Akt in the insulin signaling pathway was found to be activated in the Hamp1-/- hepatocytes to a greater extent than wild-type (WT) cells, both under basal conditions and in response to insulin. Incubation of the Hamp1-/- hepatocytes with an iron chelator attenuated these effects. There was no evidence of oxidative stress or AMPK activation in the Hamp1-/- hepatocytes. Glucose production by these cells was similar to that by WT cells. Gene expression of key gluconeogenic enzymes was decreased in these cells. In addition, they showed evidence of increased lipogenesis. CONCLUSIONS: Hepatocytes from Hamp1-/- mice showed evidence of greater sensitivity to the effects of insulin than WT hepatocytes. This may explain the insulin-sensitive phenotype that has been reported in classical hemochromatosis.

Setting the agenda for nurse leadership in India: what is missing.

BACKGROUND: Current policy priorities to strengthen the nursing sector in India have focused on increasing the number of nurses in the health system. However, the nursing sector is afflicted by other, significant problems including the low status of nurses in the hierarchy of health care professionals, low salaries, and out-dated systems of professional governance, all affecting nurses' leadership potential and ability to perform. Stronger nurse leadership has the potential to support the achievement of health system goals, especially for strengthening of primary health care, which has been recognised and addressed in several other country contexts. This research study explores the process of policy agenda-setting for nurse leadership in India, and aims to identify the structural and systemic constraints in setting the agenda for policy reforms on the issue. METHODS: Our methods included policy document review and expert interviews. We identified policy reforms proposed by different government appointed committees on issues concerning nurses' leadership and its progress. Experts' accounts were used to understand lack of progress in several nursing reform proposals and analysed using deductive thematic analysis for 'legitimacy', 'feasibility' and 'support', in line with Hall's agenda setting model. RESULTS: The absence of quantifiable evidence on the nurse leadership crisis and treatment of nursing reforms as a 'second class' issue were found to negatively influence perceptions of the legitimacy of nurse leadership reform. Feasibility is affected by the lack of representation of nurses in key positions and the absence of a nurse-specific institution, which is seen as essential for creating visibility of the issues facing the profession, their processing and planning for policy solutions. Finally, participants noted the lack of strong support from nurses themselves for these policy reforms, which they attributed to social disempowerment, and lack of professional autonomy. CONCLUSIONS: The study emphasises that the nursing empowerment needs institutional reforms to facilitate nurse's distributed leadership across the health system and to enable their collective advocacy that questions the status quo and the structures that uphold it.

Increased intracellular iron in mouse primary hepatocytes in vitro causes activation of the Akt pathway but decreases its response to insulin.

BACKGROUND: An iron-overloaded state has been reported to be associated with insulin resistance. On the other hand, conditions such as classical hemochromatosis (where iron overload occurs primarily in the liver) have been reported to be associated with increased insulin sensitivity. The reasons for these contradictory findings are unclear. In this context, the effects of increased intracellular iron per se on insulin signaling in hepatocytes are not known. METHODS: Mouse primary hepatocytes were loaded with iron in vitro by incubation with ferric ammonium citrate (FAC). Intracellular events related to insulin signaling, as well as changes in gene expression and hepatocyte glucose production (HGP), were studied in the presence and absence of insulin and/or forskolin (a glucagon mimetic). RESULTS: In vitro iron-loading of hepatocytes resulted in phosphorylation-mediated activation of Akt and AMP-activated protein kinase. This was associated with decreased basal and forskolin-stimulated HGP. Iron attenuated forskolin-mediated induction of the key gluconeogenic enzyme, glucose-6-phosphatase. It also attenuated activation of the Akt pathway in response to insulin, which was associated with decreased protein levels of insulin receptor substrates 1 and 2, constituting insulin resistance. CONCLUSIONS: Increased intracellular iron has dual effects on insulin sensitivity in hepatocytes. It increased basal activation of the Akt pathway, but decreased activation of this pathway in response to insulin. GENERAL SIGNIFICANCE: These findings may help explain why both insulin resistance and increased sensitivity have been observed in iron-overloaded states. They are of relevance to a variety of disease conditions characterized by hepatic iron overload and increased risk of diabetes.

Decreased hepatic iron in response to alcohol may contribute to alcohol-induced suppression of hepcidin.

Hepatic Fe overload has often been reported in patients with advanced alcoholic liver disease. However, it is not known clearly whether it is the effect of alcohol that is responsible for such overload. To address this lacuna, a time-course study was carried out in mice in order to determine the effect of alcohol on Fe homoeostasis. Male Swiss albino mice were pair-fed Lieber-DeCarli alcohol diet (20 % of total energy provided as alcohol) for 2, 4, 8 or 12 weeks. Expression levels of duodenal and hepatic Fe-related proteins were determined by quantitative PCR and Western blotting, as were Fe levels and parameters of oxidative stress in the liver. Alcohol induced cytochrome P4502E1 and oxidative stress in the liver. Hepatic Fe levels and ferritin protein expression dropped to significantly lower levels after 12 weeks of alcohol feeding, with no significant effects at earlier time points. This was associated, at 12 weeks, with significantly decreased liver hepcidin expression and serum hepcidin levels. Protein expressions of duodenal ferroportin (at 8 and 12 weeks) and divalent metal transporter 1 (at 8 weeks) were increased. Serum Fe levels rose progressively to significantly higher levels at 12 weeks. Histopathological examination of the liver showed mild steatosis, but no stainable Fe in mice fed alcohol for up to 12 weeks. In summary, alcohol ingestion by mice in this study affected several Fe-related parameters, but produced no hepatic Fe accumulation. On the contrary, alcohol-induced decreases in hepatic Fe levels were seen and may contribute to alcohol-induced suppression of hepcidin.

Indomethacin induces endoplasmic reticulum stress, but not apoptosis, in the rat kidney.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice. However, their use is often associated with adverse effects in the gastrointestinal tract and kidney. Our earlier work with indomethacin, a prototype NSAID, has shown that it induced oxidative stress in the kidney in rats, an event that has been postulated to contribute to pathogenesis of its adverse effects in this organ. Endoplasmic reticulum (ER) stress responses have been shown to occur in response to oxidative stress. We investigated whether this occurred in the rat kidney, in response to indomethacin. For this, Wistar rats were orally gavaged with indomethacin (20mg/kg). Markers of ER stress were studied in the kidneys 1, 12 and 24h later. GRP78, p-PERK and nuclear sXBP-1, all markers of ER stress, were found to be increased in the rat kidney at 12h, in response to indomethacin; levels of these markers fell by 24h. The effects seen at 12h were attenuated by pre-treatment with zinc, a known anti-oxidant, which has earlier been shown to ameliorate indomethacin-induced oxidative stress. Activation of an ER stress response was not associated with induction of apoptosis, as measured by markers of apoptosis such as release of cytochrome c from mitochondria into the cytosol, activation of caspases 3 and 9, cleavage of poly-ADP ribose polymerase and the presence of DNA laddering. We conclude that indomethacin-induced oxidative stress activated ER stress, but did not lead to apoptosis in the rat kidney.

Do medical students require education on issues related to plagiarism?

In the course of our professional experience, we have seen that many medical students plagiarise. We hypothesised that they do so out of ignorance and that they require formal education on the subject. With this objective in mind, we conducted a teaching session on issues related to plagiarism. As a part of this, we administered a quiz to assess their baseline knowledge on plagiarism and a questionnaire to determine their attitudes towards it. We followed this up with an interactive teaching session, in which we discussed various aspects of plagiarism. We subjected the data obtained from the quiz and questionnaire to bivariate and multivariate analysis. A total of 423 medical students participated in the study. Their average score for the quiz was 4.96±1.67 (out of 10). Age, gender and years in medical school were not significantly associated with knowledge regarding plagiarism. The knowledge scores were negatively correlated with permissive attitudes towards plagiarism and positively correlated with attitudes critical of the practice. Men had significantly higher scores on permissive attitudes compared to women . In conclusion, we found that the medical students' knowledge regarding plagiarism was limited. Those with low knowledge scores tended to have permissive attitudes towards plagiarism and were less critical of the practice. We recommend the inclusion of formal instruction on this subject in the medical curriculum, so that this form of academic misconduct can be tackled.

Indomethacin inhibits activation of endothelial nitric oxide synthase in the rat kidney: possible role of this effect in the pathogenesis of indomethacin-induced renal damage.

The clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with adverse effects in the kidney. Indomethacin, an NSAID that has been shown to induce oxidative stress in the kidney, was used to study the pathogenesis of renal damage induced by the drug in a rat model. Experimental animals were given indomethacin (20mg/kg) by oral gavage, sacrificed 1, 12 or 24h (h) later and the kidneys studied. Evidence of glomerular and tubular damage in the kidney was found in response to the drug. Renal tissue nitrite levels, a surrogate marker of nitric oxide (NO) synthesis, were significantly decreased at 12 and 24h. Indomethacin did not affect protein and mRNA levels of endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS). However, it significantly reduced the ratio of dimeric (active) to monomeric (inactive) eNOS in the kidney, 12 and 24h after drug administration. This was associated with reductions in heme content, both in renal tissue and in NOS. Heme oxygenase 1 (HO-1) mRNA (at 1 and 12h), protein (at 12 and 24h) and activity (at 1, 12 and 24h) were elevated in response to indomethacin. Nuclear translocation of Nrf2 (at 12h) and p38 MAPK signaling (at 12h and 24h), both of which are known to induce HO-1, also occurred in response to the drug. In summary, our results show that indomethacin reduced levels of activated eNOS in the kidney. This effect is possibly mediated by heme depletion, secondary to HO-1 induction that occurred downstream of Nrf2 and p38 MAPK signaling. We postulate that reduced renal eNOS activity may result in decreased NO levels, and hence reduced renal perfusion, leading to glomerular and tubular injury with subsequent renal damage.

Advancing the application of systems thinking in health: understanding the growing complexity governing immunization services in Kerala, India.

BACKGROUND: Governing immunization services in a way that achieves and maintains desired population coverage levels is complex as it involves interactions of multiple actors and contexts. In one of the Indian states, Kerala, after routine immunization had reached high coverage in the late 1990s, it started to decline in some of the districts. This paper describes an application of complex adaptive systems theory and methods to understand and explain the phenomena underlying unexpected changes in vaccination coverage. METHODS: We used qualitative methods to explore the factors underlying changes in vaccination coverage in two districts in Kerala, one with high and one with low coverage. Content analysis was guided by features inherent to complex adaptive systems such as phase transitions, feedback, path dependence, and self-organization. Causal loop diagrams were developed to depict the interactions among actors and critical events that influenced the changes in vaccination coverage. RESULTS: We identified various complex adaptive system phenomena that influenced the change in vaccination coverage levels in the two districts. Phase transition describes how initial acceptability to vaccination is replaced by a resistance in northern Kerala, which involved new actors; actors attempting to regain acceptability and others who countered it created several feedback loops. We also describe how the authorities have responded to declining immunization coverage and its impact on vaccine acceptability in the context of certain highly connected actors playing disproportionate influence over household vaccination decisions.Theoretical exposition of our findings reveals the important role of trust in health workers and institutions that shape the interactions of actors leading to complex adaptive system phenomena. CONCLUSIONS: As illustrated in this study, a complex adaptive system lens helps to uncover the 'real' drivers for change. This approach assists researchers and decision makers to systematically explore the driving forces and factors in each setting and develop appropriate and timely strategies to address them. The study calls for greater consideration of dynamics of vaccine acceptability while formulating immunization policies and program strategies. The analytical approaches adopted in this study are not only applicable to immunization or Kerala but to all complex interventions, health systems problems, and contexts.