Published evidence of the cost-effectiveness of alcohol-based handrub (ABH) for the prevention of neonatal bloodstream infections (BSI) is limited in sub-Saharan Africa. Therefore, this study evaluates the cost-effectiveness of a multimodal hand hygiene involving alcohol-based hand rub (ABH) for the prevention of neonatal BSI in a neonatal intensive care unit (NICU) setting in Ghana using data from HAI-Ghana study. Design was a before and after intervention study using economic evaluation model to assess the cost-effectiveness of a multimodal hand hygiene strategy involving alcohol-based hand rub plus soap and water compared to existing practice of using only soap and water. We measured effect and cost by subtracting outcomes without the intervention from outcomes with the intervention. The primary outcome measure is the number of neonatal BSI episode averted with the intervention and the consequent cost savings from patient and provider perspectives. The before and after intervention studies lasted four months each, spanning October 2017 to January 2018 and December 2018 to March 2019, respectively. The analysis shows that the ABH program was effective in reducing patient cost of neonatal BSI by 41.7% and BSI-attributable hospital cost by 48.5%. Further, neonatal BSI-attributable deaths and extra length of hospital stay (LOS) decreased by 73% and 50% respectively. Also, the post-intervention assessment revealed the ABH program contributed to 16% decline in the incidence of neonatal BSI at the NICU. The intervention is a simple and adaptable strategy with cost-saving potential when carefully scaled up across the country. Though the cost of the intervention may be more relative to using just soap and water for hand hygiene, the outcome is a good reason for investment into the intervention to reduce the incidence of neonatal BSI and the associated costs from patient and providers’ perspectives. The health and economic impact of hospital-acquired neonatal bloodstream infection (BSI) is enormous but often underestimated due to data constraints resulting from a lack of monitoring and reporting from hospital settings . A globaIncreasingly, the capacity of neonatal intensive care units (NICU) in under-resourced countries is overstretched due to about 10–15% incidence of hospital-acquired infections (HAI) rate among neonates , 4, and Consequently, early preventive measures are preferred globally to reduce the associated morbidity and mortality burden but also to reduce the accompanying incremental healthcare cost on families, society, and the health system. Therefore, cost-effectiveness evaluation of interventions aimed at reducing neonatal BSI and to improve quality of life has subsequently been recognized as a major input for health decision making and prioritization .A published guideline for the prevention of hospital-acquired neonatal BSI by the American Academy of Paediatrics highly recommended the use of alcohol-based handrub (ABH) technique for hand hygiene . ABH is Regardless of the increasing evidence of the potential monetary and health benefits associated with improved hand hygiene care in developed countries, very limited studies in low-and-middle income countries (LMIC) examine the cost-effectiveness of alcohol-based handrub for the prevention of neonatal BSI in NICU settings . In sub-Therefore, this study attempt to measure in monetary terms the cost-effectiveness of a multimodal hand hygiene strategy involving use of ABH compared to existing practice of using only soap and water for the prevention of neonatal BSI in the NICU in a Tertiary Hospital in Ghana. To do so, the study answered a specific question: Is the intervention cost-effective than liquid antiseptic in NICU settings?We employed a before and after intervention design to conduct a cost-effectiveness analysis (CEA) of ABH based on a simple decision model. For quality check, we report according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist for economic evaluation . The stuStudy setting was the NICU in the KBTH in Ghana. The hospital serves as the leading tertiary referral hospital in Ghana and it is located at the national capital of Accra. The NICU is managed by the Department of Child Health and has in place an Infection Prevention and Control (IPC) team managed by the Quality Assurance Unit of the hospital. Medical staff at the unit render 24-hour service interspaced by an 8-hour shift system. The unit has three cubicles with each having an admission capacity of 33 neonates at a time. Every year the NICU admits about 0.3% of all newborns in Ghana .The study population comprises neonates admitted to the neonatal intensive care unit (NICU) of the Korle Bu Teaching Hospital (KBTH). A subgroup of the population (100 in the baseline and 84 in the endline survey) with clinically diagnosed hospital-acquired BSI following positive blood cultures constitute the sample for this study within the two sampling windows (October 2017 to January 2018 and from December 2018 to March 2019). Eligibility for inclusion were BSI neonates with birth weight ≥750 grams and ≤48 hours of age at the time enrolment. Not included in the sample were BSI neonates with severe congenital malformations and those who had undergone surgical procedures. The inclusion and exclusion criteria were contingent on clinical data at the NICU. Sample size calculation was based on 80% power and 0.05 alpha .Two reasons informed the choice of the study population and subgroup. First, previous studies acknowledge the need for more empirical studies to implement cost-effective interventions for neonatal BSI in sub-Saharan Africa , 13. SecThe baseline study (pre-intervention) evaluated the cost of neonatal BSI from patient/carers and provider perspective. Total, average and marginal direct and indirect costs were reported . ConsequThis study compares the cost-effectiveness of conventional hand hygiene care (CHHC) with optimal hand hygiene care (OHHC) for the prevention and control of neonatal BSI in the NICU. In the NICU of the KBTH, CHHC represents an infection control measure in which healthcare workers practice regular handwashing with liquid antiseptic (soap and water). Caregivers of neonates mostly mothers also make an average of three contacts daily with their newborns for breastfeeding after cleaning their hands with liquid antiseptic, while medical staff (nurses and doctors) establish a countless number of contact with the neonates depending on the severity of their illness. In addition to regular handwashing, medical staff use disposable hand gloves before attending to neonates. Each neonate is kept in a cot/incubator on admission until discharged. Before admission, cots and incubators are disinfected by trained health workers to prevent bacterial transmission. All the eligible 100 participants recruited during the baseline survey received conventional hand hygiene care. Compliance was generally followed as reported elsewhere . The basAt the end of the baseline survey, a multimodal hand hygiene intervention was initiated by the NICU. It involves CHHC plus ABH, referred to in this paper as optimal hand hygiene care (OHHC). At the NICU, ABH equals 70% formulation of alcohol-based handrub used to prevent bacterial transmission and bloodstream infection among neonates. The choice of intervention followed the World Health Organisation’s multimodal hand hygiene strategy for the prevention of infectious diseases including neonatal BSI . The impWe used a simplified decision tree model comparing a cohort of neonates with and without exposure to the intervention . Our modThe primary effect measure is the proportion of neonatal BSI cases avoided with the ABH  and the attributable costs. We argued that the number of mortalities avoided and life years lost based on the estimated change in mortality risk is more uncertain due to the limited number of observations. Therefore, measurement of effectiveness assumed the incremental outcomes related to the intervention and calculated as:To analyse the attributable cost of neonatal BSI, we matched BSI neonates with non-BSI neonates based on birth weight, sex, and delivery type . For theFor indirect cost, the study measured the opportunity cost of productive lost days to parents/caregivers of neonates related to hospital admission i.e. the loss of income during admission and the subsequent 30 days after discharge. For BSI neonates who died before the 30- day post-discharge surveillance, cost was captured up to the time of death. Further detail is captured in the baseline study .We estimated hospital cost per BSI neonate as the product of the daily hospital cost and the extra LOS of 10.2 and 5.1 days as derived before and after the intervention, respectively. The procedure used for calculating the hospital cost is reported in the baseline paper . BrieflyThe cost of the intervention was calculated as the sum of all expenses incurred during the intervention, and which will be necessary for continuation of the intervention. It includes the cost of alcohol hand rub and supplies, 200 litre of ethanol, staff training allowance, etc. Cost of materials were valued at market price and the staff training allowance valued using a per diem amount.The data was collected prospectively by a team of experts in health economics with funding from the Danish Ministry of Foreign Affairs. Informed consent was sought from all participants. The study was granted ethical approval by the Institutional Review Board of the Korle Bu Teaching Hospital. Therefore, the robustness and reliability of the data lies in its credibility and quality.First, statistical background differences in characteristics of the participants were measured using chi-square statistics for categorical variables (p<0.05). This is to ensure that participants in each group were comparable. Second, we computed our primary effect based on z-test of proportions and estimated the 95% confidence intervals (95%CI) due to the slightly differences in sample size between groups. To preserve our crude estimate based on the limited sample size, we decided to report the 95% CI from the z-test. We also analysed and reported the mean and 95% CI for three indicators of severity i.e. LOS, number of blood culture tests, and outpatient visits.The incremental cost savings with the intervention was computed as the difference in patient total cohort cost i.e. post-intervention patient cost minus pre-intervention patient cost. To understand the potential impact of the ABH intervention, the estimated incremental cost was multiplied by an estimated annual number of neonatal BSI in Ghana. To examine the incremental hospital cost attributable to neonatal BSI, the estimated daily hospital cost of $99 and $102 from the pre and post intervention per neonate was multiplied by the mean extra LOS attributable to neonatal BSI. Again, we populated our decision model with the estimated parameter values using after intervention cohort as basis for calculating cost and effects with and without exposure to the intervention.An incremental patient cost-effectiveness ratio (ICER) was analysed by diving the change in patient total cohort cost obtained from the pre and post-intervention by the number of neonatal BSI cases avoided i.e. the effect gain –20. The Cost calculations were made in Ghana cedis (GH₵) and converted to 2019 purchasing power parity in United States Dollars (US$) using a web-based purchasing power parity convertor that equates the PPP value of US$1.00 to GHC1.645 . The datThe robustness of the incremental cost derived from the intervention was analysed for uncertainty using both one-way and multiway deterministic sensitivity analyses (DSA). We limited the sensitivity analysis to DSA because the 95% uncertainty intervals for our effect estimate did not overlap, which makes it enough to conclude on the effectiveness of the intervention. The input parameters include patient cost, hospital cost, and the probability of neonatal BSI pre and post-intervention. The parameters were varied using the minimum and maximum values of the 95% uncertainty intervals around the base case mean cost. Knowing how the uncertainty intervals derived from the 95%CI affect the incremental cost-effectiveness of healthcare interventions is highly recommended in the WHO guide to cost-effectiveness analysis . We usedA total of 357 and 469 neonates were admitted to the NICU during the pre and post-intervention surveys. The incidence of neonatal BSI was 28% [95% CI: 23%–33%%] and 17.9% [95%CI: 14%–21%] in the pre and post intervention groups respectively. More than half the sample were male neonates, and more than 80% and 60% were born through caesarian deliveries in the pre and post-interventions respectively. The majority of neonates were born low birth weight (≥1kg–≤2kg). There were statistically no significant differences in the background characteristics of the sub-sample for both periods .For all the incremental outcomes analysed, there was a reduction in the number of events following the implementation of the ABH intervention. Example, the rate of neonatal BSI was 28% in the baseline as opposed to 17.9% in the endline study, resulting into 16% avoidable neonatal BSI episodes. Likewise, the study recorded 73.1% reduction in BSI-attributable mortalities, 50% reduction in the mean additional LOS for BSI neonates, 43.8% reduction in the mean number of outpatient visits, and 52.1% reduction in the mean number of blood cultures for BSI neonates .The total cost of the intervention was covered with funds for the HAI-Ghana project. Approximately 66% of the intervention cost was staff-related expenses, while the remaining 34% went into the purchase of standardized supplies . The per neonate cost of the intervention per day estimated from the overall sample of 469 and the observed average LOS of 11.4 days is $3.60 per day .We disaggregated the patient cost of healthcare at the NICU into medical and non-medical costs. The medical cost relates to antibiotics, review/outpatient care, laboratory tests/blood culture, and medical consultation. Non-medical cost includes transportation, accommodation and feeding. In all the categories of cost analysed, there was a reduction following the implementation of the OHHC. For instance, the mean total cohort cost of hospitalization per BSI neonate under CHHC scenario was US$1026 as opposed to US$598.63 in the OHHC scenario. The difference resulted in $427.4 patient cost savings, equivalent to 41.7% cost saving per BSI neonate . ApplyinThe total cost of care attributable to BSI before and after the intervention equals the sum of the mean patient and hospital costs per BSI neonate multiplied by the number of BSI patients in each group. The outcome yielded an estimated ICER of approximately $3,679 cost saving per neonatal BSI avoided , suggestResults from the sensitivity analysis shows the intervention may lead to cost savings if the input parameters are varied within the 95% uncertainty intervals. Before January 2018, the NICU provide only water and soap for hand hygiene. Water flow was infrequent, occasioned by rationing from the national grid and other technical challenges. Therefore, compliance with hand hygiene was becoming a challenge vis-à-vis alarming cases of hospital-acquired infections . The WHOThe base case analysis of incremental outcomes suggests the intervention with ABH is a dominant hand hygiene strategy  that couWe observed that the intervention is dominant and the incremental cost savings is, in descending order of magnitude, sensitive to some parameters, including the probability of BSI, hospital cost, and patient cost. Nonetheless, the incidence of neonatal BSI at the NICU may depend somehow on other circumstances such as the percentage formulation of the alcohol-hand rub, ring and artificial nail wearing by medical staff, among other environmental and individual factors , 28. AlsFurther, the observed fifty percent reduction in BSI-attributable extra LOS with the intervention is 6.5 days less than has been reported in other NICU settings . HoweverOur case for investment consideration by policy-makers and healthcare providers is that assuming the intervention prevents 10% risk of neonatal BSI cases in Ghana as revealed in the base-case analysis, the estimated ICER suggests society can save in excess of $74 million annually.The strength of the study hinges on the quality and reliability of the data and the robustness of the methodology. The findings also provide a snapshot of reliable information on the trade-offs between two hand hygiene technologies for health policy decision-making, especially with regards to preventive interventions for nosocomial bloodstream infections among neonates in Ghana. To the best of our knowledge, this study is the first to do so in the context of Ghana using quality data from HAI-Ghana study.The paper did not cover the generality of the health consequences associated with neonatal BSI in Ghana. The design and data limitation constrained our ability to estimate BSI-attributable disability-adjusted life years (DALYs) and quality-adjusted life-years (QALY) for our sample, which we anticipate may contribute to an underestimation of the cost and effect associated with the intervention. Again, we only compared the cost and outcomes for a short time and did not consider future costs. The use of average cost figures may not reflect the true impact of the intervention and patient spending. Our exclusion criteria meant we excluded four patients with severe congenital malformations and three patients who had undergone surgery, which could have nuanced the cost savings somehow. Also, the study was limited to one NICU setting due to funding constraints and may limit the ability to generalise the result to the entirety of Ghana. We anticipate that fundamental differences in the pricing of goods and services i.e. transport, accommodation, feeding, drugs, etc. may affect how much patient spend on their health. Therefore, such differences should be considered when looking at the macro impact of the intervention.The study examined the cost-effectiveness of alcohol-based handrub in preventing neonatal BSI in NICU settings. On the evidence of the analysis, the study shows positive gains with respect to cost savings and neonatal health outcomes. Though the cost of the intervention may be more relative to using just soap and water for hand hygiene, the outcomes is a good reason for policy-makers and healthcare providers to invest into the intervention to reduce the incidence of hospital-acquired neonatal BSI and the associated costs from patient and providers’ perspectives.S1 Data(XLSX)Click here for additional data file.


Traditional food systems of many ethnic communities in India directly depend on their symbiotic relationship with the surrounding natural resources and the local socio-ecological and cultural dynamics. However, in the light of development activities resulting in drastic socio-ecological changes, these communities are oftentimes found stranded with over-simplified and unsustainable food systems. Using an ethnographic methodology, we present the case of Gaddis – an agro-pastoral community of Himachal Pradesh in India. In this paper, we documented the on-going trade-offs in traditional livelihoods of the Gaddis and their land use patterns that cause a significant transition in the traditional food systems. Based on our observations, we argue that mapping the shifting political ecology of resources enables a better understanding of transitioning food systems and the consequent eco-cultural changes. While doing so, we emphasize the need for revisitng the existing praxis of tribal development in India with an urgent focus on holistic socio-ecological approaches. Traditional Food Systems, Socio-ecology, Cultural Change, Land-use Pattern, Gaddi Community. Some of these communities, depending on criteria like socio-economic backwardness, geographic isolation, and cultural distinctiveness, are designated as Scheduled Tribes under Article 342 of the Indian constitution. Majority of these communities reside in vulnerable socio-ecological zones and practice traditional occupations that are in-sync with their natural environment. These occupations enable them to have symbiotic relationships with their local ecology and play a vital role in shaping their food systems. These traditional food systems (hereafter TFSs) are oftentimes the outcomes of time-tested and culturally accepted resource dependence patterns. They form the socio-ecological interface highlighting the relationships that the tribal communities have with their local ecologies. They are also reflective of the diverse provisioning skills, techniques, and cultural beliefs of the people . SimultaHowever, TFSs of the tribal communities are now found to be dwindling in the light of the current development scenario that favours the forces of industrialisation and urbanisation that result in cultural and environmental homogenisation. Numerous alterations in the distinct domains of traditional livelihoods, land use patterns and resource availability are collectively affecting the TFSs. It was also observed that the local tribes are rather quickly assimilating the mainstream food cultures due to their easy availability through Public Distribution System (PDS) since last few decades. Such practices are not only against the health of the coupled human-environment arrangements but also put the community-based resource management in jeopardy. Our study maps such declining TFSs of the Gaddi tribe of Himachal Pradesh (HP) in India, to comprehend the larger implications of such phenomena on the Gaddi socio-ecological and cultural systems.GaddiAlthough a significant body of literature exists on the Gaddis , the traHimachal Pradesh is engaged in a rapid expansion of road network for the past few decades, largely driven by the setting up of several hydro-electric power projects, mineral and slate mines along with the booming apple cultivation. These developments, on the one hand, promoted economic diversification in the state and on the other hand led to a decline in traditional occupations, and food production practices . While tAlong with mapping the pattern of Gaddi livelihood transformations that puts their traditional food systems in peril, we also consider the government interventions that look after the infrastructure of food production and distribution. For instance, measures such as the Green RevolutionIn this paper, we highlight the transitions in TFS of the Gaddis to articulate their changing socio-ecological landscape. According to the scientific studies e.g., , TFS areThis paper is developed into five sections. The first section covers an elaborate introduction that conceptually and geographically contextualises the study, followed by the second section, which presents a thematic literature review. The third section of this paper discusses the methodological orientation and procedures of data collection. Findings of the research are thematically arranged in the penultimate section while the analysis and articulation of the concluding observations are accommodated in the fifth section.22.1Food patterns specific to any community develop through several generations of lifestyle practices. Many contextual socio-ecological factors influence the way these practices evolve over a period of time. Literature enlists local practices based on ethnic identities, agro-climatic conditions, socio-cultural ethos and religion as essential factors that play a role in shaping the food choices of people . Apart fAccording to 2.2According to There are extensive records of how the traditional multi-crop regimes viably provide varied and nutritious food along with the much-needed by-products that can be recycled and reused for sustainable ends . In the A significant factor that contributes to the declining TFS is the state-run food security intervention through public distribution systems (PDS). While introducing diets of the dominant cultures among indigenous societies  these pr3This study is an outcome of an on-going ethnographic doctoral project on the Gaddis of Himachal Pradesh in India. The qualitative data presented in this paper was collected throughout 2019 in a phased manner from the villages of Bharmour tehsiln = 20), oral histories (n = 5) and focus group discussions (FGDs) (n = 3) were periodically conducted. All the willing members of the Gaddi community, irrespective of their intersectional differences, were approached for their consent to participate in the study. Consent was obtained verbally or by getting the informed consent forms signed by the participants. No specific exclusion criteria was devised for the respondents, as their physical availability oftentimes remained challenging in the difficult terrain of the study site following their seasonal mobility and the shifting settlements of their residenceFollowing a combination of convenient and snowball sampling method, qualitative data collection tools including in-depth interviews  in Himachal Pradesh under the Tribal Sub Plan scheme of 1974, Gaddis started receiving an increased development focus from the state government . A nucle4.1Gaddi traditional agro-pastoral occupation forms an excellent example of a self-subsistent food system, as this pattern is primarily based on the seasonal use of resources and complementarity between agricultural and pastoral practices. It not only ensures food security but also works as an essential adaptive strategy that helps in efficient utilisation of irregularly distributed and least productive resources .Traditionally, Gaddis rear sheep and goats by following a vertical seasonal transhumance patternGaddi pastoral occupation includes a seasonal downhill migration, which enables their regular and periodical access to the local markets. This exchange also strengthens their reciprocal relationships with the sedentary agriculturalist populations of the plains . Traditi"Currently, it's all apple cultivations everywhere in the region. Although the apple crop suits our land (which does not support extensive agriculture otherwise), it deprives us of our staple and traditional food articles. It may provide us with a pocket full of money, but at critical times of need, it would not give us proper food to eat. Bringing all the land under horticulture has left us with no scope for growing our traditional food these days. If in case some extreme natural calamity takes place and government supplies do not reach our region, we would be left with nothing to eat and all we will have remaining will just be the apples and the money". However, it has been observed that in the last few decades, Gaddis are constantly abandoning their traditional subsistent agro-pastoralism to adopt commercial horticulture and other diversified livelihood practices. Unlike earlier, a significant portion of the land in the settled villages of Bharmour region is now under apple cultivation, leaving no fallow land or crop residues for livestock grazing . This di"These jobs in the cities do not pay well and there remains a dangling sword on your head that you would be thrown out today or tomorrow. In our traditional agro-pastoralism, we are our own bosses. We can sell one animal if a need arises and manage any crisis with the income. What do these youngsters have! Even if they are earning in the cities, they ask for money from home." .The sentiments expressed above reflect the shifting cropping patterns and large-scale economic diversification resulting in changing land use patterns in the region at an accelerated pace. Maximum of the middle-aged Gaddi population we interacted with is now either engaged in private businesses or salaried jobs with less or no interest in cultivating their own fields. Furthermore, the young and the educated Gaddi are also seen to dissociate themselves with the agriculture fields and the traditional pastoral profession . They woOutmigration of the Gaddi youth for city jobs, local economic diversification and shifts towards remunerative horticulture are some of the significant changes enlisted by our respondents as factors that affect their traditional occupation in the Bharmour region of Himachal Pradesh. These changes that now people are well attuned with have an otherwise more profound and invisible negative impact affecting the food systems of the Gaddi community. A substantial decline in agro-pastoral practices has thus influenced their traditional food production and procurement processes at various levels that we discuss in the next sections.4.2Himalayan ecology and terrain are critical factors that shape the TFS of Gaddis. The extreme seasonal variance and fragmented terrace cultivations do not allow for technological experimentation, which otherwise is possible in the plains. Therefore, for an extended period, Gaddi agricultural practices remained limited to production for household consumption only . Howevermakki (Maize- Zea Mays), gehu (Wheat-Triticum aestivum), Barley (Hordeum vulgare), Bhrase (Buckwheat or Fagopyrum esculentum), Chinae (Hill millet or Panicum miliaceum), Phullan (millets), Sieul (Amaranthus amaranthoides), Kodra  Urad (Phaseolus radiates) and Kulth (Dolichos biflorus) ((cheedh) and walnuts (akhrot) were used to obtain the cooking oil through traditional methods . Additionally, the local staple diet also included good portions of meat, as it was readily available. However, with the declining pastoral profession, meat consumption has reduced because of the limited local supply and a drastic increase in its price.Despite the limited seasonal agriculture, the staple food patterns of Gaddis traditionally included a diversity of food crops grown variably over Rabi and Kharif season in their local fields . It mainly comprised of iflorus) . Along wRajmah (Phaseolus Vulgaris), Potatoes and few other varieties of lentils .Additionally, these changes in land use pattern are also affecting the social structure of the Gaddi community that remains closely associated with their TFS. Historically, the Gaddi community followed a joint family pattern where the land possessions were held within the extended family . This paHowever, with the changing times and increasing social distance within the families, the land has been further subdivided into fragmented holdings. This has led to an infrastructural change in the region where new houses and buildings are coming up to accommodate separate nuclear families that earlier lived collectively under one roof as one household. The disintegration of family structure has also created inadequacy of labour as well as land among the Gaddis, making it challenging for them to pursue their traditional subsistence agricultural activities.4.3Amidst the socio-ecological and cultural changes stated above that adversely impact the local food production, another major area of concern remains the current source of food procurement. The response to this conundrum appears straightforward, however it remains multifaceted and layered in nature. Currently, the Gaddi community is relying on external sources for their food procurement in the absence of traditional agro-pastoral activities. These sources, including the expanding markets, and government run food security programmes like PDS have become the primary source and for some the only source for food procurement. Although PDS has worked a great deal in ensuring a continuous food supply, it ignores the socio-ecological significance of TFS of the Gaddi community. For instance, unlike their TFS, the PDS system operating in the Bharmour region supplies the residents with rice, lentils, wheat, sugar and cooking oil, that did not form a significant part of their staple food patterns till a few years back. All the food articles that the subsidised ration shops redistribute under PDS were alien to their TFS. "Everything we procure from the market is a product of chemicals. Even vegetables are injected with god knows what chemicals. It has led to many health-related issues in the people, including increased cases of sugar (Diabetes), high blood pressure and youth having no stamina. They (younger generation) can't even walk in the plains for a longer time let alone climb the mountains." .The local Gaddi respondents also reported several repercussions in terms of health, land use and agricultural practices because of such drastic changes. One of the old male Gaddi respondents informed us that-To sum up our findings, the following table presents the changes that the Gaddi TFS has undergone see . These c5It is evident that the Gaddis are rapidly transitioning to the diets of their surrounding dominant cultures without realising the long-term impacts of these changes on the quality of their life as well as their local socio-ecology. The traditionally grown food crops that included many climatically resilient varieties of millets are fast disappearing from their local food regimes. The same millets are now paradoxically emerging as 'superfoods' in the dominant food cultures of urban India. Gaddi community has started losing out on its traditional food culture and its agro-biodiversity only recently- but the steep transition curve that has come to stay in its place is indicating a trend observed throughout the global south. This trend points towards the irreversible loss of biological and ecological complexity at the regional level that adversely impacts the symbiotic relationship of communities (like the Gaddi) with their native habitats. This level of steep transition not only creates an imbalance, but also alienates the indigenous communities like Gaddis from their traditional habitats and practices.Gaddi traditional agro-pastoral systems stressed the sustainable need fulfilment aspects . HoweverThe political ecology of resource access and control determines the food choices that people make, and it also directs the course of cultural change within their communities . The shiWe do recognise that the socio-ecological practices change over a period of time for any given community . HoweverAayushi Malhotra: Conceptualization, Data collection, analysis and interpretation, Writing and revision.Sailaja Nandigama: Conceptualization, Data analysis and interpretation, Writing and revision.Kumar Sankar Bhattacharya: Data interpretation, Writing and revision.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper.


Ectopic thyroid most commonly presents in the midline and is typically associated with the absence of an orthotopic thyroid. Less commonly, ectopic thyroid can present in the lateral neck, typically with a coexisting orthotopic thyroid and abnormal pathology in either the ectopic or orthotopic thyroid tissue. This paper describes a rare case of a benign, ectopic thyroid in the lateral neck (level II) associated with a normal, benign orthotopic thyroid. This report illustrates clinical pearls for the management of this unusual entity. Ectopic thyroid is uncommon, with an estimated prevalence of 1 in 100,000, and involves the presence of thyroid tissue in an abnormal location, most often in the midline neck near the base of the tongue with an absence of an orthotopic thyroid -6. We deA 49-year-old female presented to our clinic with a painless mass in the right neck that had been asymptomatic and stable in size for 1.5 years. The mass had been first noted incidentally by her dentist. She had no history of radiation exposure and no personal or family history of head and neck cancer. On examination, the mass was soft, non-tender, mobile, and deep to the sternocleidomastoid muscle. Ultrasound Figure , and magThe patient’s case was discussed at our multi-disciplinary thyroid and parathyroid tumor board, which determined that her clinical presentation was most consistent with stage I cT1N1b regionally metastatic papillary thyroid microcarcinoma (PTC) to the right lateral neck without an identified primary lesion on preoperative imaging. It was determined that the primary malignant lesion would likely be found in the orthotopic thyroid gland on final pathology. Therefore, the tumor board recommended performing a total thyroidectomy, central neck dissection, and right lateral neck dissection. The risks, benefits, and alternatives to surgery were discussed with the patient, including the alternative surgical option of a staged approach with initial right neck dissection followed by total thyroidectomy and central neck dissection if the pathology of the neck nodes was positive for thyroid cancer. The patient elected to proceed with upfront total thyroidectomy and neck dissections. She was scheduled for a total thyroidectomy with central and right lateral neck dissections. Intraoperatively, a 3 cm, gray, right neck mass (level II) was noted. The appearance of the mass was smooth and atypical for cervical metastasis of papillary thyroid cancer. Frozen section analysis of the mass demonstrated bland thyroid tissue epithelium without evidence of malignancy. Based on the frozen section results and the atypical appearance of the level II neck mass, the operation was stopped with a plan to stage a completion thyroidectomy and left central neck dissection if final histopathology demonstrated malignancy. The portions of the scheduled surgeries that were performed were right lateral neck dissection, right hemithyroidectomy, and right-central compartment neck dissection.Final histopathology demonstrated the right neck mass to be a benign thyroid nodule with cystic alterations and no evidence of malignancy Figure . The necTo the best of our knowledge, this is the first report in the English-language literature of a benign, ectopic thyroid in the lateral neck (levels II-IV) associated with a normal, benign orthotopic thyroid. Two prior reports describe benign ectopic thyroid in the lateral neck associated with an orthotopic, multinodular thyroid goiter ,3. ThreeThe embryologic development of ectopic thyroid in the lateral neck remains unclear. One theory is that ectopic thyroid tissue in the lateral neck originates from the ultimobranchial bodies, the neural crest progenitors of parafollicular C cells, in the lateral anlage of the thyroid gland. By contrast, midline ectopic thyroid is thought to arise from endodermal remnants left along the thyroglossal duct tract during the descent of the primordial thyroid gland .Presentations of ectopic thyroid in the lateral neck often mimic the clinical presentation of cervical metastasis of a thyroid malignancy with unknown primary. Detection of thyroid tissue outside of the central neck compartment (level VI) rightly warrants strong suspicion for cervical metastasis of a primary thyroid malignancy until proven otherwise. The rare presentation of an off-midline ectopic thyroid is important to be aware of in cases in which preoperative imaging does not reveal a primary thyroid malignant lesion, and there is strong clinical suspicion for a benign lesion based on intraoperative findings. In such cases, a staged approach can be considered with upfront excisional biopsy and frozen section analysis prior to staged completion of thyroidectomy and central neck dissection. This approach can balance safe and effective oncologic care with reducing the morbidity of potentially avoidable surgery that would predispose the patient to lifelong high-dose thyroid hormone replacement.Most cases of ectopic thyroid present in the midline with an absence of an orthotopic thyroid; rarely, ectopic thyroid can present in the lateral neck. This is the first report of a benign, ectopic thyroid in the lateral neck (level II) associated with a normal orthotopic thyroid. The presentation of thyroid tissue in the lateral neck rightly warrants suspicion for cervical metastasis of a primary orthotopic thyroid malignancy. However, the absence of a primary lesion on preoperative imaging and benign intraoperative characteristics, including frozen section analysis, suggests that a staged surgical approach can be considered. In our case, a staged surgical approach confirmed the diagnosis of off-midline ectopic thyroid and spared the patient completion thyroidectomy and the associated morbidity of lifelong dependence on high-dose thyroid hormone supplementation. This report contributes to the limited literature on lateral neck ectopic thyroids and refines their characterization to note their typical coexistence with an orthotopic thyroid, in contrast with midline ectopic thyroids.


This clock effect controls electrical synapses between rods and cones so that rod-cone electrical coupling is minimal in the day and robust at night. The increase in rod-cone coupling at night improves the signal-to-noise ratio and the reliability of very dim multi-photon light responses, thereby enhancing detection of large dim objects on moonless nights.Conversely, maintained (30 min) bright illumination in the day compared to maintained darkness releases sufficient dopamine to activate low-affinity dopamine D1 receptors on cone-bipolar cell dendrites. This non-circadian light/dark adaptive process regulates the function of GABAA receptors on ON-cone-bipolar cell dendrites so that the receptive field (RF) surround of the cells is strong following maintained bright illumination but minimal following maintained darkness. The increase in surround strength in the day following maintained bright illumination enhances the detection of edges and fine spatial details.The vertebrate retina, like most other brain regions, undergoes relatively slow alterations in neural signaling in response to gradual changes in physiological conditions , or in response to gradual changes in environmental conditions . As occurs elsewhere in the brain, the modulatory processes that mediate slow adaptation in the retina are driven by extrinsic signals  and/or by intrinsic signals such as those of the circadian (24-h) clock in the retina. This review article describes and discusses the extrinsic and intrinsic modulatory processes that enable neural circuits in the retina to optimize their visual performance throughout day and night as the ambient light level changes by ~10 billion-fold. In the first synaptic layer of the retina, cone photoreceptor cells form gap junctions with rods and signal cone-bipolar and horizontal cells (HCs). Distinct extrinsic and intrinsic modulatory processes in this synaptic layer are mediated by long-range feedback of the neuromodulator dopamine. Dopamine is released by dopaminergic cells, interneurons whose cell bodies are located in the second synaptic layer of the retina. Distinct actions of dopamine modulate chemical and electrical synapses in day and night. The retinal circadian clock increases dopamine release in the day compared to night, activating high-affinity dopamine D A major goal of research on the retina and other brain regions is to understand the mechanisms that underlie the modulation of neuronal properties , synaptic communication, and neural network activity in response to changes in the environment or physiological conditions. Most regions of the central nervous system including the retina undergo relatively slow alterations in neural signaling in response to gradual changes in physiological conditions, as when activity changes to rest, or in response to gradual changes in environmental conditions, as when day changes into night. The retinal response to daily changes in the visual environment due to rotation of the Earth are particularly intriguing because the ambient (background) light level changes a great deal (~10 billion-fold) and because visual performance needs at midday are very different than those on a moonless night. Survival requires high acuity at midday and sensitivity to very dim objects on moonless nights. As occurs elsewhere in the brain, the modulatory processes that mediate slow adaptation in the retina are driven by extrinsic signals  and/or by intrinsic signals such as those of the circadian (24-h) clock in the retina.This review will focus on extrinsic and intrinsic signal modulation in the first synaptic layer (or outer plexiform layer) of the retina. In this portion of the retina, cone photoreceptor cells initiate visual processing when the ambient (background) illumination is bright and rod photoreceptor cells initiate visual processing when it is very dim or dark  increases adenylyl cyclase activity, whereas activation of the D2 receptor family (Gi receptor) decreases adenylyl cyclase activity , which function as dopamine autoreceptors, i.e., activation of D2Rs decreases dopamine release  surround. Specifically, it has been shown recently that dopamine D1Rs mediate light-dark modulation of the strength of ON-cBC receptive field surrounds by regulating GABAARs on the dendrites of the cells . In the second system, the extracellular concentration of dopamine, by activating low-affinity D1Rs, constitutes a response to extrinsic changes in the visual environment . We focus for the remainder of this review, on these dopamine-mediated extrinsic and intrinsic neuromodulatory processes, which involve these two dopamine receptor systems.These above observations of how dopamine acts as a neuromodulator in the retina thus provide evidence for the notion that there are two dopamine receptor systems in the retina. In one of these systems, dopamine, by activating high-affinity DLimulus, inhibited each other’s light responses . Under these conditions, ON-cBCs produced center and surround light responses, including surround activation and surround antagonism  when dopamine was in the bath but not when D1Rs were blocked or when dopamine was not added to the bath  and during hyperpolarizing surround light responses  and that hyperpolarizing responses to surround stimulation can be attributed to reduced GABAAR excitation. It is worth noting that these results are inconsistent with the idea that surround stimulation evokes a GABA-mediated conductance that inhibits the cells  is such that EGABA is more positive than the resting membrane potential, possibly due to activity of the chloride cotransporter NKCC on the dendrites of the cells  changing the membrane potential of HCs modulates the membrane potential of nearby BCs and the spiking of nearby ganglion cells; and (2) artificially hyperpolarizing HCs, as occurs when they respond to light stimuli, antagonizes the center light responses of nearby BCs and ganglion cells  HCs express GABA  and during hyperpolarizing surround light responses  and that hyperpolarizing surround responses can be attributed to reduced GABAAR excitation. Moreover, it is well documented that bright light uncouples HCs by activating their D1Rs , which are on cones but not HCs  or dopaminergic amacrine cells  activates cone Dunctions . In conthen cHCs .It is important to emphasize that cones (and cHCs) are able to respond to very dim scotopic light stimuli at night in the dark due to the action of the retinal clock. In other words, cones and post-synaptic neurons in cone pathways respond to very dim (low scotopic) light stimuli at night because the conductance of the rod-cone electrical synapse is high. This phenomenon was observed by maintaining retinas under dark-adapted conditions with no illumination present brighter than low mesopic  on photoreceptors, there is downstream activation of cAMP and PKA and hence increased rod-cone coupling  and intrinsic (D4R) dopamine systems function in a complementary manner and unfold slowly, i.e., .they only need to keep pace with the rotation of the Earth. In the outer retina, D1Rs and D4Rs, which have opposite effects on intracellular cAMP/PKA when activated  are located on rods and cones, and D1Rs (but not D4Rs) are located on the dendrites of cone-connected BCs and HCs (Witkovsky, via D4Rs (Ribelayga et al., 1Rs on the dendrites of cBCs and HCs in goldfish and rabbits regulates GABAAR expression and activity on the dendrites of these cells (Witkovsky, 1Rs and D4Rs in the outer retina discussed in this review can be generalized across species that contain both rods and cones.Finally, it is important to note that the modulatory effects of dopamine in the outer retina are likely conserved across vertebrate species, including mammals and non-mammals. Specifically, circadian pathway components and effects and the location of DMG and SM wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Parasitic nematodes infect almost all forms of life. In the human context, parasites are one of the major causative factors for physical and intellectual growth retardation in the developing world. In the agricultural setting, parasites have a great economic impact through a reduction in livestock performance or control cost. The main method of controlling these devastating conditions is the use of anthelmintic drugs. Unfortunately, there are only a few anthelmintic drug classes available in the market and significant resistance has developed in most of the parasitic species of livestock. Therefore, development of new anthelmintics with different modes of action is critical for sustainable parasitic control in the future. The drug development pipeline is broadly limited to two types of molecules, namely synthetic compounds and natural plant products. Compared to synthetic compounds, natural products are highly diverse, and many have historically proven valuable in folk medicine to treat various gastrointestinal ailments. This review focus on the use of traditional knowledge-based plant extracts in the development of new therapeutic leads, the approaches used as screening techniques, and common bottlenecks and opportunities in plant-based anthelmintic drug discovery. Parasites depend on their hosts for physiological and metabolic needs during the infective stages. Most host-parasite relationships have endured for thousands of years and often display remarkable host-parasite specificity. In this parasite-host co-evolutionary arms race, parasites have the advantage of short generation times and generally large number of progeny compared to their host species. As a result, many parasites can overcome the host resistance strategies  and treaDespite improved healthcare systems around the globe over recent decades, parasitic infections are still strikingly common among humans . It is eHelminths infect humans when they contact parasitic eggs or larvae, which thrive in warm and moist soil . DespiteSimilar to the human experience, animals are also impacted by parasites that result in significant economic loss. Livestock production systems are important capital assets that provide more than half of the global agricultural production ,25. ParaThere are two general strategies to control parasitic infection among animals. One is the application of good animal husbandry or hygienic practices in order to minimise the introduction and spread of parasitic infections and the second is the use of chemicals/drugs to clear the infection. In the 18th century, chemical treatments based on the use of crude plant extracts or metals that had the ability to “irritate” the parasitic worm and/or remove them mechanically from the gut were introduced . Some ofOnchocerca vulgaris .,92.91,92Target-based and mechanism-based drug screening requires the identification of a specific target predicted to have a major impact on the development or function of the parasite. Once a target is identified, screening for new inhibitors or antagonistic compounds that impact target function follows and is accelerated by High Throughput Screening (HTS) methods. Generally, in these screens, chemical libraries are tested on known or predicted parasitic targets for possible interaction ,98. ThisHaemonchus contortus [Whole organism-based approaches are used to detect potential compounds that initiate paralysis, abnormalities in feeding and reproduction or death in the target species . Phenotyontortus . Despiteontortus .Another popular strategy to search for novel molecules is based on evidence through ethnopharmacology. Ethnopharmacology is scientific validation of the uses of traditional or “folk” medicine including medicinal plants used by the ancient healers. Traditionally, plants have been used for the treatment of helminth parasites as a home remedy in the form of crude preparations or after random testing on parasitic problems of already prepared herbal medicines for other diseases ,102,103.An alternative strategy for new anthelminthic identification is the reverse pharmacological approach which involves target-based drug screening techniques. In this approach, plants are examined, and libraries of molecules are established. The molecules are tested on putative targets, i.e., enzymes or receptors involved in important biological activities in a cell. These chemical libraries are either based on random plants (unbiased compound libraries) or traditional use/knowledge-based libraries . Some moHaemonchus contortus, Taenina crassicep, Ascaris suum, Ascaris lumbricoides, Taenia solium, Schistosoma mansoni and non-parasitic free-living nematodes like Caenorhabditis elegans and Pheretima posthuman  difficulties in access and supply, (2) complexities of natural product chemistry, (3) concerns about intellectual property rights, and (4) greater optimism of success with collections of compounds prepared by combinatorial chemistry methods ,121,122.Although there has been increased research around the development of anthelmintic drugs, there is a continual need to find new drug agents with new modes of action. Major challenges that exist in the development of anthelminthic drugs include poor understanding of the complicated nature of the life cycles, parasite quantification techniques for effective screening and the ability to develop effective models that represent the complete life cycle of the target parasite . FurtherPresently, most anthelmintic therapy and drug development focus on the parasite adult stages and larvae obtained from the vectors. Some of these key parasitic stages are difficult to obtain in significant numbers and researchers are often compelled to use the more easily available stages which might not reflect the real parasitic stage in the host environment. This results in a poor understanding of the effects of plant-based drugs on the authentic life cycle stages of the parasite .C. elegans and parasitic worm stages that are maintained in the laboratory environment such as H. contortus larval stages in which their viability or behaviour were examined upon exposure to libraries of drugs. However, these screens have various limitations like poor identification of a specific drug target, use of live worms and the use of conventional microscopy for assessment of worm viability [Use of high-throughput screening is the most common method of investigating libraries of drugs. A limitation in anthelmintic drug discovery is the lack of helminth cell lines able to express the receptors or target ion channels needed for high-throughput screening . This haiability . Plant eiability . The useiability . These miability ,125. In per se.When plant extracts are tested for anthelmintic activities, they may contain a high concentration of active compounds. However, this may not correspond to the concentration of active compounds consumed by the host in their diets when they are fed with crude extracts . FurtherDue to these common bottlenecks observed in the extraction of the plant compounds, variations in the screening results, poor specificity and sensitivity, and the requirement for a thorough knowledge of the biology, the screening and development of anthelmintic drugs from plant-based extracts is often considered a high-risk activity for pharmaceutical companies. The minimal benefits and great challenges involved in the screening of plant-based compounds are common factors for poor interest observed by commercial companies. Tapping into the traditional knowledge of the diverse communities/cultures that use plant extracts in their traditional medicine may provide a more beneficial targeted approach compared to high-throughput screening of large synthetic libraries.Despite the accepted shortcomings of commercial development of natural products, the vast array of chemically and structurally diverse molecules they exhibit provide an outstanding source of novel compounds for drug discovery . The 201


This paper explores the determinants of debt financing choices among small-scale manufacturing enterprises in Ethiopia—with special focus on the role of government policies. The study exploits survey data gathered from 1321 enterprises in the Amhara region of Ethiopia and employs conditional mixed process (CMP) system estimation technique to test the effect of public policy on firm debt levels. The relevant econometric findings confirm that policy activism through the provision of training and related intervention schemes boosts debt utilization in startup finance mix while it lowers the probability of firms' falling into higher debt levels over time. The results also show that enterprises that had some debt mix in their startup capital are more likely to be in higher debt categories than those enterprises that kick start exclusively with their own internal resources. In addition, the findings also reveal that self-reported profitability, firm age, and ownership structure have strong effects on the degree of firms’ indebtedness. One major bottleneck to the survival and growth of SMEs is their relatively large default rates. One strand of the existing literature shows that firm default rates are strongly correlated with debt levels. As default rates driven by high debt levels have devastating implications for creditors, debtors, and regulators, it is very important to understand the determinants of debt levels. This study is the first to apply conditional mixed process system estimation on firm level data from Ethiopia to test the effects of government policies on debt level choices. Debt financing; Small-scale enterprises; Ordered probit; Conditional mixed process; Ethiopia. Micro, Over the past couple of decades, the government of Ethiopia has given considerable attention to small-scale enterprises in general and to manufacturing firms in particular as an important instrument of poverty reduction and job creation in urban areas. For instance, the Central Statistical Agency of Ethiopia  reportedth pillar components that capture financial system development show a rank of 103/141 for domestic credit to private sector as percentage of GDP; 114/141 for access to SME financing and 124/141 for soundness of banks  indicated that Ethiopia's overall competitiveness rank was 126 out of 141 countries. In addition, the report's 9of banks . Ethiopiof banks .Currently, the financial system in Ethiopia is dominated by banks, insurance companies and microfinance institutions without functioning stock markets. The banking sector is characterized by dormantAnother important bottleneck to the survival and growth of SMEs is their relatively large default rates. While there is mounting evidence about the positive effects of debt financing on several metrics of firm growth  theory that suggests that financing options are haunted by the need to ponder the relative costs and benefits of utilizing external financial resources. The model views a firm's choice of optimal debt-equity mix as a function of three parameters: taxation, liquidation risks, and conflicts among key agents. If the firm decides to use debt, for instance, it enjoys reduction in its corporate tax obligations and boosts the after-tax income at its disposal. In consequence, tax advantage and the market value of the firm co-move in the same direction as a result of firms' efforts to align the tax advantages of more debt with increasing probability of bankruptcy risks .The third major framework in the capital structure literature is the pecking order theory (POT) that was introduced by 2.2Empirically numerous studies have examined the sources, patterns and implications of different financing preferences of firms. Concentrating on Brazilian small and medium firms, In the context of developing countries, Beyond the standard determinants, some scholars have accentuated the importance of owner-manager specific characteristics. For instance, in a study of small and medium enterprises in Malaysia, Still very important, the policy environment in which firms operate can also shape their financing choices. For instance, it is now widely recognized that tax policy considerations and probability of bankruptcy risks influence firm financing choices . OverescIn Ethiopia, federal and local governments provide several financial and non-financial support packages as part of an effort to encourage small-scale enterprise development as a tool for poverty reduction and job creation. These packages include training, technology transfer, and related business development services (BDS) as well as organizational support to the youth by the government during business formation process . These gH1Access to business development services (BDS) has no effect on debt financing level.H2Government support in group business formation process has no effect on debt financing level.In addition to the inconclusive nature of the existing evidence on the debt-policy nexus, there are very few studies on determinants of leverage in low-income economies in general and in Ethiopia in particular. The only study we are aware of is In light of the above discussion, the major hypotheses the study aims to test are the following:33.1The data used in this paper is part of a broader dataset collected in 2016/17 fiscal year as part of a mega research project to assess the status of small and micro manufacturing enterprises in the Amhara region of Ethiopia. Available information was collected by administering structured questionnaires to focal persons (including owners and managers) in 1381 small and micro manufacturing enterprises. These enterprises were scattered across eleven zonal capital towns of the same region. Ultimately 1321 enterprises filled in and returned the distributed questionnaires giving rise to a response rate of about 96 percent. The available information was gathered from the owners/managers of the target firms by employing multi-stage stratified simple random sampling techniques. In the first stage, the Amhara region was selected as this region housed the university that supported the specific research as part of an effort to understand the socio-economic problems and contribute to the local community development needs. Inclusion of other regions in the country was not possible because of financial constraints. In the second stage, the team leaders decided to cover all the eleven zonal capital towns of Amhara region as the vast majority of the small and micro manufacturing enterprises was concentrated in those towns. In each town, the enumerators contacted the concerned technical, vocational, and enterprise development office personnel for lists of the target firms. In the final stage, the questionnaires were distributed to proportionally allocated and randomly selected enterprises to make sure that each sub-sector receives fair representation in the total sample.3.2Drawing on Many previous studies e.g.  studied In 3.33.3.1Several studies have used level categories to study degree of indebtedness among individuals, households, and firms e.g. . In this3.3.2This study incorporates numerous independent variables drawing from the existing literature. In order to capture potential effects of government policy, the study includes two proxy variables, namely, access to government-provided training, technology transfer and related business development services (BDS) and existence of local government initiative in organizing job seekers to form groups and start business. Finally, the study includes other standard control variables that affect current degree of firms’ indebtedness (see 44.1Descriptive statistics of the major model variables are presented in debt inertia in the sense that those enterprises that get into business with some liability are more likely to have access to credit market and to maintain a certain degree of indebtedness over time.Stylized facts on the sampled firms’ financing profiles4.24.2.1Firm age (with those below three years as a benchmark) has non-linear effect on leverage positions of target firms. For instance, those firms older than 8 years have about 12% additional probability of being in no-debt category while the corresponding probabilities for being in moderate and high levels of leverage decline by about 8% and 3.4%, respectively. The marginal effects are significant at 95 percent confidence level. These findings indicate that maturity has inverse relationship with the likelihood of using higher levels of debt in clear contrast with the prediction of the POT. The present finding is inconsistent with the findings of The marginal effects in 4.2.2The marginal effects presented in The results in Second, the sign and significance of startup financing mix, firm age, and profitability are also preserved in the system estimation results. Third, the ownership variable, which was insignificant so far, now enters significantly at 95 percent confidence level. This specific result confirms that individually owned firms see lower probabilities of being in higher debt levels. The correlation between ownership structure of the firm and financing patterns was also confirmed by previous studies e.g. .Finally, firm size, ownership structure, government support in business formation process, education attainment, and perception about the role of rental cost are significant drivers of the mix of startup finance. For instance, having college education raises the probability of using debt in startup financing by about 37%, a result significant at 95 percent confidence level. This implies that education affects leverage level indirectly through its effect on the choice of startup finance mix. This contradicts the results of single equation studies that showed that education has direct effect on firm debt levels .5Understanding the patterns and drivers of firm balance sheet composition is important from macro- and micro-economic points of view. This paper explores the determinants of debt levels among small-scale manufacturing enterprises in Ethiopia. The study relies on survey data gathered from Amhara region during 2016/17 fiscal year and employs descriptive and conditional mixed process (CMP) estimation techniques to isolate the effects of both standard and heterodox factors on firm financing preferences. The relevant econometric findings confirm that policy activism through the provision of training and related intervention schemes lower the probability of firms' falling into higher debt levels. The results also show that enterprises that had some debt mix in their startup capital are more likely to be in higher debt categories than those enterprises that kick start exclusively with their own internal resources. In addition, the findings also reveal that self-reported profitability, firm age, and ownership structure have strong effects on the degree of firms' indebtedness. Since policy activism was found to have significant negative relationship with the likelihood of falling into higher debt levels, concerned policymakers should strengthen existing financial and non-financial policy intervention packages in order to lower the probability of firms’ falling into destabilizing debt levels.Wondemhunegn Ezezew: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.Ermias Berihun: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.Fentahun Baylie and Derbew Kenubeh: Analyzed and interpreted the data; Wrote the paper.10.13039/501100007861University of Gondar, Gondar, Ethiopia.This research was supported by the Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper.


The Hong Kong-specific criteria have been established in 2019 to assess potentially inappropriate medication (PIM) use in older adults and improve the local prescribing quality. The aim of this study was to compare the adaptive versions of the Hong Kong-specific criteria and 2015 Beers criteria for assessing the prevalence and correlates of PIM use in Hong Kong older patients.A cross-sectional study was performed from January 1, 2014 to December 31, 2014 using the Hospital Authority (HA) database. A total of 489,301 older patients aged 65 years and older visiting general outpatient clinics (GOPCs) during the study period were included in the study. Two categories of PIM use included in the Hong Kong-specific criteria and 2015 Beers criteria, i.e. PIMs independent of diagnoses and PIMs considering specific medical conditions, were adapted to assess the prevalence of PIM use among the study sample. Characteristics of PIM users and the most frequently prescribed PIMs were investigated for each set of the criteria. Factors associated with PIM use were identified using the stepwise multivariable logistic regression analysis.The adaptive Hong Kong-specific criteria could detect a higher prevalence of patients exposed to at least one PIM than that assessed by the adaptive Beers criteria (49.5% vs 47.5%). Meanwhile, the adaptive Hong Kong-specific criteria could identify a higher rate of patients exposed to PIMs independent of diagnoses (48.1% vs 46.8%) and PIMs considering specific medical conditions (7.3% vs 4.9%) compared with that of the adaptive Beers criteria. The most frequently prescribed PIMs detected by the adaptive Beers criteria were all included in the adaptive Hong Kong-specific criteria. The strongest factor associated with PIM use was number of different medications prescribed. Patients with female gender, aged 65 ~ 74 years, a larger number of GOPC visits, and more than six diagnoses were associated with greater risk of PIM use, whereas advancing age was associated with lower risk of PIM use.The adaptive Hong Kong-specific criteria could detect a higher prevalence of PIM use than the adaptive Beers criteria in older adults visiting GOPCs in Hong Kong. It is necessary to update the prevalence and correlates of PIM use regularly in older adults to monitor the burden of PIM use and identify vulnerable patients who need further interventions.The online version contains supplementary material available at 10.1186/s12877-021-02324-5. Potentially inappropriate medication (PIM) use occurs when patients are prescribed a drug that has a high risk of adverse drug events (ADEs) as compared to its potential benefits, especially when safer or more effective therapeutic alternatives are available . These AIn Hong Kong, the Hospital Authority (HA) is responsible for the management of all the public health services, including public hospitals, Specialist Out-patient Clinics (SOPCs), and General Out-patient Clinics (GOPCs) . ApproxiExplicit PIM lists are defined as drug or disease oriented firm standards developed from literature review, expert opinions or consensus techniques . They caA cross-sectional study was conducted from January 1, 2014 to December 31, 2014 using the HA database. Patients’ electronic health records were collected by doctors using the HA computer system. Since the HA computer system includes all the patients who use public health services in Hong Kong, the data extracted from the HA database are highly reliable. Each patient was allocated a unique identity code so as to link up their clinical records across different datasets.In this study, a cohort of older adults aged 65 years or older visiting GOPCs in 2014 were extracted from the general outpatient dataset. All the diagnoses for each patient visiting GOPCs during the study period were considered in the current study and coded using the International Classification of Primary Care, Second edition (ICPC-2) system. The prescribing information of the study population was collected from the medication datasets, which included drug prescriptions in the public primary care setting. The medication datasets provided information on generic drug names of medications originating from the HA drug formulary without any detail of indication, dose or therapy duration. The records on healthcare service use including GOPC visits and hospital admissions were extracted from the general outpatient dataset and inpatient dataset, respectively. Each consultation episode per patient during the study period was identified by a unique sequence number. The data we used for this study were retrospective, pre-existing and de-identified; any sensitive information on patients, doctors or clinics was not accessible.PIM use in the current study was identified by the 2015 Beers criteria and Hong Kong-specific criteria, respectively. The operational definition of PIM use for this study used two categories of PIMs, namely, PIMs independent of diagnoses and PIMs considering specific medical conditions, for they were both included in the two sets of criteria. Since the prescription records in the database were originated from the HA drug formulary, the availability of PIMs in the context of the public primary care setting was examined by this formulary. PIMs that were not covered by the HA drug formulary were excluded from the current study. Due to the incomplete prescribing information provided by the HA database, PIMs with any restriction or exception in terms of dose, indication or therapy duration defined by the two sets of criteria were not taken into account. Additionally, the certain PIMs considering specific medical conditions without an exclusive ICPC-2 code corresponding to its medical condition were also excluded from the current study. After applying the inclusion and exclusion criteria, the adaptive versions of the Beers criteria and Hong Kong-specific criteria were presented in the Additional file p value < 0.05. R version 3.6.3 software was used for all statistical analyses.The prevalence and associated factors of PIM use were analyzed separately for the two sets of criteria. The most common PIMs that were prescribed in more than 1% of the study population were listed for each set of criteria. The following patient variables were investigated for their association with PIM use: gender, age, number of different drugs prescribed, number of diagnoses, number of GOPC visits within the year, and number of hospital admissions within the year. Chi-square tests were performed for categorical variables to test the correlations between patient characteristics and PIM use. Stepwise multivariable logistic regression models were used to identify factors associated with PIM use at GOPCs in older adults. Adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were reported. The statistical significance was set at As shown in Table The basic characteristics and the ability to detect PIMs between the Beers criteria and the Hong Kong-specific criteria were compared in Table The characteristics of PIM users assessed by the adaptive versions of the Beers criteria and Hong Kong-specific criteria were described in Table The factors associated with having at least one PIM use were identified in the multivariable logistic regression analysis by applying the adaptive versions of the Beers criteria and Hong Kong-specific criteria, respectively Table . FemalesTable This is the first population-based study assessing PIM use in older adults using an explicit tool developed in Hong Kong. The ability of the Hong Kong-specific criteria in detecting PIMs was also compared with another set of well-established criteria, i.e. the Beers criteria. Both adaptive versions of the criteria identified a high prevalence of PIM use in older adults vising GOPCs in Hong Kong. Furthermore, the adaptive Hong Kong-specific criteria could detect a higher prevalence of PIM use, including PIMs independent of diagnoses and PIMs considering specific medical conditions, than that evaluated by the adaptive Beers criteria in the local context. Similar patterns of risk factors associated with PIM use were identified by applying the two sets of criteria. In the multivariable regression analysis, the findings showed that PIM use was associated with female gender, larger number of drugs prescribed, more frequent GOPC visits, and more than six diagnoses, which were generally consistent with the results from previous studies –31. HoweThe prevalence rates of PIM use assessed in the current study were relatively higher than those reported in western countries in the primary care setting (ranging from 2.90 to 40.7%) , 29 as wAmong the most frequently prescribed PIMs in older adults visiting GOPCs, all the PIMs identified by the adaptive Beers criteria were included in the adaptive Hong Kong-specific criteria. Despite the similarities on the most common PIMs assessed by the two sets of criteria, the adaptive Hong Kong-specific criteria could detect certain PIMs that the adaptive Beers criteria failed to identify, involving metoclopramide, zopiclone, and medications exacerbating chronic constipation. In fact, metoclopramide was incorporated in the 2015 Beers criteria, however, it was excluded from the adaptive Beers criteria for this drug could be used exceptionally for the treatment of gastroparesis in older adults according to the consensus of the Beers expert panel. In addition, the criterion of medications exacerbating chronic constipation has been removed from the Beers criteria since 2012 because the Beers expert panel believes this drug-disease combination is not particularly problematic to older adults. Furthermore, the adaptive Beers criteria failed to detect zopiclone in the context of Hong Kong mainly because this drug was not available in the drug market of the US. Although the Hong Kong-specific criteria were established in the context of HA drug formulary, most of the individual PIMs in this PIM list were also included in the Beers criteria and other country-specific PIM criteria. Therefore, it is feasible to apply the Hong Kong-specific criteria to measure the appropriateness of prescribing in other regions and make international comparisons.The study population of this research was representative by including nearly half of older adults in Hong Kong. Few studies have used population-based data to assess the burden of PIM use in Hong Kong. Furthermore, most of previous studies using explicit criteria for PIM evaluations only employed the category of PIMs independent of diagnoses due to incomplete clinical information . In addiIn this study, the key findings can inform policies for the healthcare system of Hong Kong and contribute to the improvement of the quality of prescribing in the local context. Analysis of the prevalence and correlates of PIM use in the current study can contribute to the enhancement of prescribing quality by quantifying the burden of PIM use in Hong Kong at the population level and identifying vulnerable patients who require further interventions. Education on prescribers should be strengthened to raise their awareness on the importance of pharmacotherapy for older patients, particularly in older adults who are exposed to polypharmacy. Apart from preparing and distributing medications, the role of pharmacists could be expanded to review medication lists and provide counseling services for vulnerable older patients in hospital and community settings. Because all the medications from the Hong Kong-specific criteria are available in the HA drug formulary, this assessment tool can be integrated into the HA computer system for warning the use of high-risk medications and providing therapeutic alternatives. The regular update of the HA drug formulary should consider including fewer PIMs listed in the Hong Kong-specific criteria and purchasing more alternatives.In conclusion, the adaptive Hong Kong-specific criteria could detect a higher prevalence of PIM use than the adaptive Beers criteria in older adults visiting GOPCs in Hong Kong. Similar patterns of risk factors associated with PIM use were identified by applying the two sets of criteria. Patients with female gender, polypharmacy, larger number of GOPC visits, and more than six diagnoses were more likely to receive PIMs, whereas advancing age was associated with lower risk of PIM use. It is necessary to update the prevalence and correlates of PIM use on a routine basis in Hong Kong older patients to monitor the burden of PIM use and identify vulnerable patients who need further interventions.Additional file 1. Adaptive Beers PIM listAdditional file 2. Adaptive Hong Kong-specific PIM list


Non-Hodgkin lymphoma (NHL) increased continuously since the last century in developed countries. While they are considered as disease in elder ages, a remarkable increasing incidence is also observed in German children and juveniles. The higher rates are interpreted by the changes in classification because diseases such as chronic lymphocytic leukaemia were also identified as NHL. Considerable rates of NHL were found in nuclear workers and liquidators of Chernobyl, i.e. in cases of low-dose chronical exposures. In Germany, we noticed three workers who developed NHL after decontamination of nuclear facilities. The bone marrow is generally considered as target organ for ionizing radiation, but NHL is obviously induced in the whole pool of lymphocytes. Therefore, the dosimetry in cases of typical occupational external and internal exposure must be revised. A high radiation sensitivity for NHL is a possible suspect and likely reason which may partly explain the continuous rise of the diseases in populations underlying the current increases of medical diagnostic exposure. NHL is also induced in children and juveniles with a history of diagnostic X-rays. Because many cell types are involved in the immune reaction of the circulating cellular system which may undergo malignant transformation, there are also many types of non-Hodgkin lymphoma (NHL). They were re-classified by IARC of the WHO . The chaIn former times, it was believed by experts that radiation-induced NHL could be expected only after high doses as in cohorts of the Japanese A-bomb survivors, after radiation therapy, or in patients exposed to thorium dioxide used as contrast medium . SystemaObservations of excess incident cases of NHL in occupationally exposed persons became more frequent in the last decades and led often to surprisingly high relative risk rates, among them large cohorts of so-called liquidators. These are survivors of about 800,000 men who were deployed by the Soviet Union for shielding and decontamination tasks after the explosion of the Chernobyl reactor in 1986.Chronic lymphocytic leukaemia (CLL) was formerly considered as non-radiogenic, based on a lack of findings in the Japanese A-bomb survivors. This dogma was criticized by Richardson and co-workers in 2005 . Later oWe noticed three cases suffering from illness of B-lymphocyte proliferation (2 CLL and one B-cell lymphoma) who were involved in the decontamination of closed nuclear establishments, since Germany began to dismantle the installations of nuclear energy. The cluster of cases gave reason to evaluate the upcoming knowledge about radiation-induced NHL.The men we refer to had worked in several nuclear enterprises, and also in a facility producing nuclear fuel rods including mixed oxide fuel assemblies (MOX) containing enriched uranium and plutonium. Their working periods and diagnoses are shown in Table According to biomonitoring data, they were exposed to penetrating gamma radiation of 116, 108 and 46 mSv  Any dose contribution by incorporated radionuclides was estimated to be very low by the Governmental Association of Occupational Insurances (Berufsgenossenschaft für Rohstoffe und chemische Industrie).Between 1996 and 2006, the 3 patients had been deployed by their same employer to the same former facility for fuel assemblies before their jobs in the decontamination. The employer documented that the places for decontamination had contained MOX fuel. This was certainly done in order to point to the special risks of plutonium, which delivers high organ doses in the case of incorporation. Indeed, we derived from some sporadic measurements by whole body counting, in urine and from the presence of neutrons, that there must have occurred incorporation of uranium and plutonium, probably by inhalation of radioactive dust. The indices for a remarkable internal dose contribution were discussed in a former paper .The clustering of the diseases which are normally very rare in ages up to 52 points towards an origin by occupational exposure.German regulations for recognition and compensation of radiation-induced occupational diseases still regard NHL and CLL as different entities and they are assumed to be originated in tissues of low radiation sensitivity . This evSignificant excess of NHL in the Japanese A-bomb survivors was not reported before 1994, and only in men . This maThe LSS is the usual reference and is related to the direct penetrating radiations by gamma rays and neutrons. A possible contribution by radioactive fallout or residual radiation by neutron activation in the grounds or other materials is assumed to be neglectable. The update of the incidence in 2013 . Study No. 11 in workers of the British reprocessing plant Sellafield combines, however, lymphomas and multiple myelomas . It founThe increase in flight personnel (No. 13) shown by SIR=2.49 (1.03–6.05) is surprising considering the rather low official estimates of their exposure and the short follow-up of <19.3 years . It corrThe incidence study in liquidators (No. 15) refers to a combined collective of men from Belarus, Russia and Baltic countries . The estCLL were found to be the most frequent form of leukaemia in liquidators . This isThe exposure of uranium miners as well as of workers in processing facilities for uranium and radium by radon and uranium/radium dust is probably not really to quantify because of the problems with accumulation in the lymph nodes after incorporation (Nos. 17–19).Lymphomas as a causally related effect were found in former  and recen=120) resulted in non-significant increase; for NHL (n=13), the odds ratio was 1.48 (0.66 to 3.32). Dose estimates were not given. The authors suggest cautious use of diagnostic imaging procedures to the abdomen/pelvis of the mother during pregnancy and in children at very young ages.Cancer cases after exposure in utero . Other cancers occurring after birth were also studied.Bithell and Stewart  refer onNHL can certainly be induced by low doses of ionizing radiation received by the lymphatic tissues which are of high relative radiation sensitivity. Precise radiation risks are not available, however, even in cases of complete homogenous dose distribution because of the varying classification of the diseases over time. If only parts of the body are exposed, any dose estimation will be unsafe because the target lymphocytes are distributed all over the circulatory system in varying concentrations. Especially in cases of incorporation of radioactivity by macrophages, any dose estimation for NHL will become close to impossible.The survey of data from low-dose exposures Table  and our From the data in Table