University of Khartoum

A consequence of the growing number of empirical studies in software engineering is the need to adopt systematic approaches to assessing and aggregating research outcomes in order to provide a balanced and objective summary of research evidence for a particular topic. The paper reports experiences with applying one such approach, the practice of systematic literature review, to the published studies relevant to topics within the software engineering domain. The systematic literature review process is summarised, a number of reviews being undertaken by the authors and others are described and some lessons about the applicability of this practice to software engineering are extracted. The basic systematic literature review process seems appropriate to software engineering and the preparation and validation of a review protocol in advance of a review activity is especially valuable. The paper highlights areas where some adaptation of the process to accommodate the domain-specific characteristics of software engineering is needed as well as areas where improvements to current software engineering infrastructure and practices would enhance its applicability. In particular, infrastructure support provided by software engineering indexing databases is inadequate. Also, the quality of abstracts is poor; it is usually not possible to judge the relevance of a study from a review of the abstract alone.

Nature is perceived and valued in starkly different and oftenconflicting ways. This paper presents the rationale for theinclusive valuation of nature's contributions to people (NCP) indecision making, as well as broad methodological steps fordoing so. While developed within the context of theIntergovernmental Platform on Biodiversity and Ecosystem Services (IPBES), this approach is more widely applicable toinitiatives at the knowledge?policy interface, which require apluralistic approach to recognizing the diversity of values. Weargue that transformative practices aiming at sustainablefutures would benefit from embracing such diversity, which require recognizing and addressing power relationships across stake holder groups that hold different values on human nature relations and NCP

Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (approximately 71%), European (approximately 13%), and other African (approximately 8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies.

BACKGROUND: The massive abundance of studies relating to tropical medicine and health has increased strikingly over the last few decades. In the field of tropical medicine and health, a well-conducted systematic review and meta-analysis (SR/MA) is considered a feasible solution for keeping clinicians abreast of current evidence-based medicine. Understanding of SR/MA steps is of paramount importance for its conduction. It is not easy to be done as there are obstacles that could face the researcher. To solve those hindrances, this methodology study aimed to provide a step-by-step approach mainly for beginners and junior researchers, in the field of tropical medicine and other health care fields, on how to properly conduct a SR/MA, in which all the steps here depicts our experience and expertise combined with the already well-known and accepted international guidance.We suggest that all steps of SR/MA should be done independently by 2-3 reviewers' discussion, to ensure data quality and accuracy. CONCLUSION: SR/MA steps include the development of research question, forming criteria, search strategy, searching databases, protocol registration, title, abstract, full-text screening, manual searching, extracting data, quality assessment, data checking, statistical analysis, double data checking, and manuscript writing.

Almost half of the total organic carbon (C) in terrestrial ecosystems is stored in forest soils. By altering rates of input or release of C from soils, forest management activities can influence soil C stocks in forests. In this review, we synthesize current evidence regarding the influences of 13 common forest management practices on forest soil C stocks. Afforestation of former croplands generally increases soil C stocks, whereas on former grasslands and peatlands, soil C stocks are unchanged or even reduced following afforestation. The conversion of primary forests to secondary forests generally reduces soil C stocks, particularly if the land is converted to an agricultural land-use prior to reforestation. Harvesting, particularly clear-cut harvesting, generally results in a reduction in soil C stocks, particularly in the forest floor and upper mineral soil. Removal of residues by harvesting whole-trees and stumps negatively affects soil C stocks. Soil disturbance from site preparation decreases soil C stocks, particularly in the organic top soil, however improved growth of tree seedlings may outweigh soil C losses over a rotation. Nitrogen (N) addition has an overall positive effect on soil C stocks across a wide range of forest ecosystems. Likewise, higher stocks and faster accumulation of soil C occur under tree species with N-fixing associates. Stocks and accumulation rates of soil C also differ under different tree species, with coniferous species accumulating more C in the forest floor and broadleaved species tending to store more C in the mineral soil. There is some evidence that increased tree species diversity could positively affect soil C stocks in temperate and subtropical forests, but tree species identity, particularly N-fixing species, seems to have a stronger impact on soil C stocks than tree species diversity. Management of stand density and thinning have small effects on forest soil C stocks. In forests with high populations of ungulate herbivores, reduction in herbivory levels can increase soil C stocks. Removal of plant biomass for fodder and fuel is related to a reduction in the soil C stocks. Fire management practices such as prescribed burning reduce soil C stocks, but less so than wildfires which are more intense. For each practice, we identify existing gaps in knowledge and suggest research to address the gaps.

Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer.

Feeding 9-10 billion people by 2050 and preventing dangerous climate change are two of the greatest challenges facing humanity. Both challenges must be met while reducing the impact of land management on ecosystem services that deliver vital goods and services, and support human health and well-being. Few studies to date have considered the interactions between these challenges. In this study we briefly outline the challenges, review the supply- and demand-side climate mitigation potential available in the Agriculture, Forestry and Other Land Use AFOLU sector and options for delivering food security. We briefly outline some of the synergies and trade-offs afforded by mitigation practices, before presenting an assessment of the mitigation potential possible in the AFOLU sector under possible future scenarios in which demand-side measures codeliver to aid food security. We conclude that while supply-side mitigation measures, such as changes in land management, might either enhance or negatively impact food security, demand-side mitigation measures, such as reduced waste or demand for livestock products, should benefit both food security and greenhouse gas (GHG) mitigation. Demand-side measures offer a greater potential (1.5-15.6 Gt CO2 -eq. yr(-1) ) in meeting both challenges than do supply-side measures (1.5-4.3 Gt CO2 -eq. yr(-1) at carbon prices between 20 and 100 US$ tCO2 -eq. yr(-1) ), but given the enormity of challenges, all options need to be considered. Supply-side measures should be implemented immediately, focussing on those that allow the production of more agricultural product per unit of input. For demand-side measures, given the difficulties in their implementation and lag in their effectiveness, policy should be introduced quickly, and should aim to codeliver to other policy agenda, such as improving environmental quality or improving dietary health. These problems facing humanity in the 21st Century are extremely challenging, and policy that addresses multiple objectives is required now more than ever.

INTRODUCTION Constipation is a chronic problem in many patients all over the world. In some groups of patients such as the elderly, constipation is a significant health care problem, but in the majority of cases chronic constipation is an aggravating, but not life threatening or debilitating, complaint that can be managed in primary care with cost-effective control of symptoms. The terminology associated with constipation is problematic. There are 2 pathophysiologies, which differ in principle but overlap: disorders of transit and evacuation disorders. The first can arise secondary to the second, and the second can sometimes follow from the first. This guideline focuses on adult patients and does not specifically discuss children or special groups of patients (such as those with spinal cord injury). Cascades: A Resource-sensitive Approach A gold standard approach is feasible for regions and countries in which the full range of diagnostic tests and medical treatment options are available for the management of all types and subtypes of constipation. A cascade is a hierarchical set of diagnostic, therapeutic, and management options for dealing with risk and disease, ranked according to the resources available. DEFINITION AND PATHOGENESIS The word “constipation” has several meanings, and the way it is used may differ not only between patients but also between different cultures and regions. In a Swedish population study, it was found that a need to take laxatives was the most common conception of constipation (57% of respondents). In the same study, women (41%) were twice as likely as men (21%) to regard infrequent bowel motions as representing constipation, whereas equal proportions of men and women regarded hard stools (43%), straining during bowel movements (24%), and pain when passing a motion (23%) as representing constipation. Depending on various factors—the diagnostic definition, demographic factors, and group sampling—constipation surveys show a prevalence of between 1% and >20% in western populations. In studies of the elderly population, up to 20% of community-dwelling individuals and 50% of institutionalized elderly persons reported symptoms. Functional constipation is generally defined as a disorder characterized by persistent difficult or seemingly incomplete defecation, and/or infrequent bowel movements (once every 3 to 4 d or less) in the absence of alarm symptoms or secondary causes. Differences in the medical definition and variations in the reported symptoms make it difficult to provide reliable epidemiologic data. Pathogenesis and Risk Factors Functional constipation can have many different causes, ranging from changes in diet, physical activity, or lifestyle to primary motor dysfunctions due to colonic myopathy or neuropathy. Constipation can also be secondary to evacuation disorder. Evacuation disorder may be associated with a paradoxical anal contraction or involuntary anal spasm, which may be an acquired behavioral disorder of defecation in two thirds of patients (Table 1).TABLE 1: Pathophysiology of Functional ConstipationAlthough physical exercise and a high-fiber diet may be protective, the following factors increase the risk of constipation (the association may not be causative): Aging (but constipation is not a physiological consequence of normal aging) Depression Inactivity Low calorie intake Low income and low education level Number of medications being taken (independent adverse effect profiles) Physical and sexual abuse Female sex—higher incidence of self-reported constipation in women Associated Conditions and Medications (Tables 2 and 3)TABLE 2: Possible Causes and Constipation-associated ConditionsTABLE 3: Medications Associated With ConstipationDIAGNOSIS Constipation is a common condition, and although a minority of patients seek medical care, in the United States alone this accounts for several million physician visits per year, whereas in the United Kingdom more than 13 million general practitioner prescriptions were written for laxatives in 2006. Gastrointestinal specialist help should focus on efficiently applying health care resources by identifying those patients who are likely to benefit from specialized diagnostic evaluation and treatment. Diagnostic Criteria for Functional Constipation An international panel of experts developed uniform criteria for the diagnosis of constipation—the Rome III criteria (Table 4).TABLE 4: Rome III Criteria for Functional ConstipationPatient Evaluation The medical history and physical examination in constipation patients should focus on identifying possible causative conditions and alarm symptoms. Stool consistency: This is regarded as a better indicator of colon transit than stool frequency (Fig. 1). Patient's description of constipation symptoms, symptom diary Bloating, pain, malaise Nature of stools Bowel movements Prolonged/excessive straining Unsatisfactory defecation Laxative use, past and present, frequency and dosage Current conditions, medical history, recent surgery, psychiatric illness Patient's lifestyle, dietary fiber, and fluid intake Use of suppositories or enemas, other medications (prescription or over-the-counter) Physical examination: Gastrointestinal mass Anorectal inspection: Fecal impaction Stricture, rectal prolapse, rectocele Paradoxical or nonrelaxing puborectalis activity Rectal mass If indicated: blood tests—biochemical profile, complete blood count, calcium, glucose, and thyroid function FIGURE 1: The Bristol Stool Form Scale: A measure to assist patients in reporting on stool consistency. Reproduced from http://commons.wikimedia.org/wiki/File:Bristol_Stool_Chart.png. © 1997 Informa Healthcare.Alarm Symptoms (Table 5)TABLE 5: Alarm Symptoms in ConstipationIndications for Screening Tests Laboratory studies, imaging or endoscopy, and function tests are only indicated in patients with severe chronic constipation or alarm symptoms (Table 6).TABLE 6: Physiologic Tests for Chronic ConstipationTransit Measurement The 5-day marker retention study is a simple method for measuring colonic transit. Markers are ingested on one occasion and the remaining markers are counted on a plain abdominal radiograph 120 hours later. If >20% of the markers remain in the colon, transit is delayed. Distal accumulation of markers may indicate an evacuation disorder, and in typical cases of slow-transit constipation almost all markers remain and markers are seen in both the right and the left colon. Several companies produce markers, but markers can also be made from a patient-safe radiopaque tube by cutting it into small pieces (2 to 3 mm in length). A suitable number of markers (20 to 24) can be placed in gelatin capsules to facilitate ingestion. Clinical Evaluation Classification of the patient's constipation should be possible on the basis of the medical history and appropriate examination and testing (Table 7).TABLE 7: Constipation Categories Based on Clinical EvaluationCascade Options for Investigating Severe and Treatment-refractory Constipation Cascade: a hierarchical set of diagnostic, therapeutic, and management options for dealing with risk and disease, ranked according to the resources available. Level 1: Limited resources (a) Medical history and general physical examination (b) Anorectal examination, 1-week bowel habit diary card (c) Transit study using radiopaque markers (d) Balloon expulsion test Level 2: Medium resources (a) Medical history and general physical examination (b) Anorectal examination, 1-week bowel habit diary card (c) Transit study using radiopaque markers (d) Balloon expulsion test or defecography Level 3: Extensive resources (a) Medical history and general physical examination (b) Anorectal examination, 1-week bowel habit diary card (c) Transit study using radiopaque markers (d) Defecography or magnetic resonance proctography (e) Anorectal manometry (f) Sphincter electromyography TREATMENT Scheme for General Management of Constipation (Table 8)TABLE 8: General Management of ConstipationSymptomatic Approach If organic and secondary constipation have been evaluated and excluded, most cases can be managed adequately with a symptomatic approach. A graded approach to treatment is based on recommending changes in lifestyle and diet, stopping or reducing medications that cause constipation, and administering fiber supplementation or other bulk-forming agents. A gradual increase in fiber (either as standardized supplements or incorporated in the diet) and fluid intake is generally recommended. The second step in the graded approach is to add osmotic laxatives. The best evidence is for the use of polyethylene glycol, but there is also good evidence for lactulose. The new drugs, lubiprostone and linaclotide, act by stimulating ileal secretion and thus increasing fecal water. Prucalopride is also approved in many countries and in Europe. The third step includes stimulant laxatives, enemas, and prokinetic drugs. Stimulant laxatives can be given orally or rectally to stimulate colorectal motor activity. Prokinetic drugs are also meant to increase the propulsive activity of the colon, but in contrast to stimulant laxatives, which should only be taken occasionally; they are designed to be taken daily. Diet and Supplements Dietary modification may consist of a high-fiber diet (25 g of fiber) and fluid supplementation (up to 1.5 to 2.0 L/d) and may improve stool frequency and decrease the need for laxatives. There is no evidence that dietary and lifestyle measures have any effect on constipation in the elderly persons; fiber supplements and simple osmotic laxatives are usually an adequate approach for constipation in these patients. In patients with colonic dilation, fiber supplementation should be avoided. Psyllium supplements and lactulose may be appropriate for the treatment of chronic constipation. Medication Evacuation disorders respond poorly to standard oral laxative programs. If an evacuation disorder plays a considerable role in constipation, biofeedback and pelvic muscle training may be considered. Critical success factors are the patient's level of motivation, the frequency of the training program, and participation of a behavioral psychologist and dietitian. If a dietary approach fails, polyethylene glycol (17 g polyethylene glycol laxative for 14 d) or lubiprostone (24 mg twice daily) can be used to promote bowel function in patients with chronic constipation. Prokinetic agents (eg, the 5-HT4 receptor agonist prucalopride) can be used in constipation-predominant irritable bowel syndrome. Simple laxative agents, such as milk of magnesia, senna, bisacodyl, and stool softeners are a reasonable choice for treating constipation. Surgery If there is persistent treatment failure in slow-transit constipation, then carefully selected, well-evaluated, and informed patients may benefit from total colectomy with ileorectal anastomosis. The exceptional indication for colectomy must be established in a specialized and experienced tertiary center. Disappointing results may be seen, with fecal incontinence due to surgery and recurrent constipation, especially in patients with evacuation disorder. Only very few patients benefit from a (reversible) colostomy to treat constipation. Evidence-based Summary (Table 9)TABLE 9: Summary: Evidence Base for the Treatment of Constipation*Cascade Options for Treatment of Chronic Constipation The following cascade is intended for patients with chronic constipation without alarm symptoms and with little or no suspicion of an evacuation disorder. The main symptoms would be hard stools and/or infrequent bowel movements. Level 1: Limited resources (a) Dietary advice (fiber and fluid) (b) Fiber supplementation (c) Milk of magnesia (magnesium hydroxide in an aqueous solution) (d) Stimulant laxatives (bisacodyl better than senna) for temporary use Level 2: Medium resources (a) Dietary advice (fiber and fluid) (b) Fiber supplementation, psyllium (c) Milk of magnesia, lactulose, macrogol (d) Stimulant laxatives for temporary use Level 3: Extensive resources (a) Dietary advice (fiber and fluid) (b) Psyllium or lactulose (c) Macrogol or lubiprostone (d) Prokinetics (prucalopride) (e) Stimulant laxatives (bisacodyl or sodium picosulfate) Cascade Options for Treatment of Evacuation Disorders This cascade is for patients with chronic constipation without alarm symptoms, but with suspicion of an evacuation disorder. The main symptoms would be prolonged straining, a feeling of incomplete evacuation, thin stools, a feeling of blockage, or failure of treatment for constipation with hard stools. Level 1: Limited resources (a) Dietary and behavioral advice (fiber, fluid, timed bowel training) (b) Therapy for chronic constipation Level 2: Medium resources (a) Dietary and behavioral advice (fiber, fluid, timed bowel training) (b) Therapy for chronic constipation (c) Biofeedback therapy Level 3: Extensive resources (a) Dietary and behavioral advice (fiber, fluid, timed bowel training) (b) Therapy for chronic constipation (c) Biofeedback therapy (d) Surgical evaluation

Agriculture, Forestry, and Other Land Use (AFOLU) is unique among the sectors considered in this volume, since the mitigation potential is derived from both an enhancement of removals of greenhouse gases (GHG), as well as reduction of emissions through management of land and livestock (robust evidence; high agreement). The land provides food that feeds the Earth’s human population of ca. 7 billion, fibre for a variety of purposes, livelihoods for billions of people worldwide, and is a critical resource for sustainable development in many regions. Agriculture is frequently central to the livelihoods of many social groups, especially in developing countries where it often accounts for a significant share of production. In addition to food and fibre, the land provides a multitude of ecosystem services; climate change mitigation is just one of many that are vital to human well-being (robust evidence; high agreement). Mitigation options in the AFOLU sector, therefore, need to be assessed, as far as possible, for their potential impact on all other services provided by land. [Section 11.1]

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

From the early 1900s, visceral leishmaniasis (VL; kala-azar) has been among the most important health problems in Sudan, particularly in the main endemic area in the eastern and central regions. Several major epidemics have occurred, the most recent--in Western Upper Nile province in southern Sudan, detected in 1988--claiming over 100,000 lives. The disease spread to other areas that were previously not known to be endemic for VL. A major upsurge in the number of cases was noted in the endemic area. These events triggered renewed interest in the disease. Epidemiological and entomological studies confirmed Phlebotomus orientalis as the vector in several parts of the country, typically associated with Acacia seyal and Balanites aegyptiaca vegetation. Infection rates with Leishmania were high, but subject to seasonal variation, as were the numbers of sand flies. Parasites isolated from humans and sand flies belonged to three zymodemes (MON-18, MON-30 and MON-82), which all belong to the L. donovani sensu lato cluster. Transmission dynamics have not been elucidated fully; heavy transmission in relatively scarcely populated areas such as Dinder national park suggested zoonotic transmission whereas the large numbers of patients with post kala-azar dermal leishmaniasis (PKDL) in heavily affected villages may indicate a human reservoir and anthroponotic transmission. Clinical presentation in adults and in children did not differ significantly, except that children were more anaemic. Fever, weight loss, hepato-splenomegaly and lymphadenopathy were the most common findings. PKDL was much more common than expected (56% of patients with VL developed PKDL), but other post-VL manifestations were also found affecting the eyes (uveitis, conjunctivitis, blepharitis), nasal and/or oral mucosa. Evaluation of diagnostic methods showed that parasitological diagnosis should still be the mainstay in diagnosis, with sensitivities for lymph node, bone marrow and spleen aspirates of 58%, 70% and 96%, respectively. Simple, cheap serological tests are needed. The direct agglutination test (DAT) had a sensitivity of 72%, specificity of 94%, positive predictive value of 78% and negative predictive value of 92%. As with other serological tests, the DAT cannot distinguish between active disease, subclinical infection or past infection. The introduction of freeze-dried antigen and control sera greatly improved the practicality and accuracy of the DAT in the field. An enzyme-linked immunosorbent assay using recombinant K39 antigen had higher sensitivity than DAT (93%). The polymerase chain reaction using peripheral blood gave a sensitivity of 70-93% and was more sensitive than microscopy of lymph node or bone marrow aspirates in patients with suspected VL. The leishmanin skin test (LST) was typically negative during active VL and converted to positive in c. 80% of patients 6 months after treatment. Immunological studies showed that both Th1 and Th2 cell responses could be demonstrated in lymph nodes from VL patients as evidenced by the presence of messenger ribonucleic acid for interleukin (IL)-10, interferon gamma and IL-2. Treatment of peripheral blood mononuclear cells from VL patients with IL-12 was found to drive the immune response toward a Th1 type response with the production of interferon gamma, indicating a potential therapeutic role for IL-12. VL responded well to treatment with sodium stibogluconate, which is still the first line drug at a dose of 20 mg/kg intravenously or intramuscularly per day for 15-30 d. Side effects and resistance were rare. Liposomal amphotericin B was effective, with few side effects. Control measures have not been implemented. Based on observations that VL does not occur in individuals who have a positive LST, probably because of previous cutaneous leishmaniasis, a vaccine containing heat-killed L. major promastigotes is currently undergoing a phase III trial.

Abstract. The Intergovernmental Technical Panel on Soils has completed the first State of the World's Soil Resources Report. Globally soil erosion was identified as the gravest threat, leading to deteriorating water quality in developed regions and to lowering of crop yields in many developing regions. We need to increase nitrogen and phosphorus fertilizer use in infertile tropical and semi-tropical soils – the regions where the most food insecurity among us are found – while reducing global use of these products overall. Stores of soil organic carbon are critical in the global carbon balance, and national governments must set specific targets to stabilize or ideally increase soil organic carbon stores. Finally the quality of soil information available for policy formulation must be improved – the regional assessments in the State of the World's Soil Resources Report frequently base their evaluations on studies from the 1990s based on observations made in the 1980s or earlier.

In this paper, a slope stability analysis for steep banks is used in conjunction with a method to calculate lateral erosion distance, to predict bank stability response to lateral erosion or bed degradation. The failure plane angle, failure block width, and volume of failed material per unit channel length may be calculated for the critical case. These parameters define the bank geometry following failure and form the starting point for subsequent analyses. The calculation procedure is illustrated by a worked example. Following mass failure slump, debris accumulates at the bank toe. The debris is removed by lateral erosion prior to further oversteepening or degradation generating further mass failures. Any process‐based model for channel width adjustment must account for the combined effects of lateral erosion and mass instability in producing bank instability. The approach adopted here represents a marked improvement over earlier work, which does not account for changes in bank geometry due to lateral erosion prior to mass failure. The engineering applications are presented in a companion paper.

A polymerase chain reaction and single-strand conformation polymorphism determination (PCR-SSCP) was used to detect deoxyribonucleic acid sequence polymorphisms in the transcribed non-coding regions between the small and large sub-unit ribosomal ribonucleic acid (rRNA) genes in Leishmania donovani from 63 clinical samples collected in eastern Sudan, between April 1997 and October 1998. Specific Leishmania primers were used to amplify the internal transcribed spacer (ITS) regions of L. donovani isolates directly from clinical samples spotted on filter papers. Amplification products were subsequently analysed by SSCP. Eleven polymorphic patterns were detected in the first part of the spacer, the ITS1 region, and were sequenced. Most of the changes were due to deletions of adenine bases and AT pairs within the first 192 nucleotides of the ITS region. This is the first application of PCR-linked SSCP analysis for the detection of population variation with direct display of sequence variation in parasitologically positive clinical samples spotted on filter paper. Culturing the parasite is thus not required, which is beneficial particularly in epidemiological studies based on field work where obtaining cultures can be extremely difficult.

Lockdown measures have been introduced worldwide to contain the transmission of COVID-19. However, the term 'lockdown' is not well-defined. Indeed, WHO's reference to 'so-called lockdown measures' indicates the absence of a clear and universally accepted definition of the term 'lockdown'. We propose a definition of 'lockdown' based on a two-by-two matrix that categorises different communicable disease measures based on whether they are compulsory or voluntary; and whether they are targeted at identifiable individuals or facilities, or whether they are applied indiscriminately to a general population or area. Using this definition, we describe the design, timing and implementation of lockdown measures in nine countries in sub-Saharan Africa: Ghana, Nigeria, South Africa, Sierra Leone, Sudan, Tanzania, Uganda, Zambia and Zimbabwe. While there were some commonalities in the implementation of lockdown across these countries, a more notable finding was the variation in the design, timing and implementation of lockdown measures. We also found that the number of reported cases is heavily dependent on the number of tests carried out, and that testing rates ranged from 2031 to 63 928 per million population up until 7 September 2020. The reported number of COVID-19 deaths per million population also varies (0.4 to 250 up until 7 September 2020), but is generally low when compared with countries in Europe and North America. While lockdown measures may have helped inhibit community transmission, the pattern and nature of the epidemic remains unclear. However, there are signs of lockdown harming health by affecting the functioning of the health system and causing social and economic disruption.

We have found that an important Th2 cytokine, IL-10, is produced by tissues from patients acutely infected with Leishmania donovani. In all individuals tested, IL-10 mRNA production was increased in lymph nodes taken during acute disease over that observed in postacute samples. In contrast, both pre- and posttreatment lymph nodes had readily detected mRNA for IFN-gamma and IL-2. A down-regulating effect of IL-10 on leishmania-induced proliferative responses was demonstrated when Hu rIL-10 was added to cultures of PBMC from clinically cured individuals. PBMC from individuals with acute visceral leishmaniasis responded to stimulation with leishmania lysate by producing IL-10 mRNA. Simultaneously cultured PBMC collected from the same patients after successful chemotherapy produced no detectable IL-10 mRNA after leishmania antigen stimulation. Neutralizing anti-IL-10 mAb added to PBMC from patients with acute visceral leishmaniasis markedly increased the proliferative response to leishmania lysate. Finally, we observed mRNA for IL-10 and IFN-gamma concurrently in a lesion from a patient with post-kala-azar dermal leishmaniasis (PKDL). These results indicate the production of IL-10 during L. donovani infection, and suggest a role for this cytokine in the regulation of immune responsiveness during visceral leishmaniasis.

We investigated whether the proinflammatory T cell cytokines IL-17 and IL-22 are induced by human mycobacterial infection. Remarkably, >20% of specific cytokine-producing CD4(+) T cells in peripheral blood of healthy, mycobacteria-exposed adults expressed IL-17 or IL-22. Specific IL-17- and IL-22-producing CD4(+) T cells were distinct from each other and from Th1 cytokine-producing cells. These cells had phenotypic characteristics of long-lived central memory cells. In patients with tuberculosis disease, peripheral blood frequencies of these cells were reduced, whereas bronchoalveolar lavage fluid contained higher levels of IL-22 protein compared with healthy controls. IL-17 was not detected in this fluid, which may be due to suppression by Th1 cytokines, as PBMC IL-17 production was inhibited by IFN-gamma in vitro. However, Th1 cytokines had no effect on IL-22 production in vitro. Our results imply that the magnitude and complexity of the anti-mycobacterial immune response have historically been underestimated. IL-17- and IL-22-producing CD4(+) T cells may play important roles in the human immune response to mycobacteria.

Interspecific polymorphisms of the 16S rRNA gene (rDNA) are widely used for species identification of mycobacteria. 16S rDNA sequences, however, do not vary greatly within a species, and they are either indistinguishable in some species, for example, in Mycobacterium kansasii and M. gastri, or highly similar, for example, in M. malmoense and M. szulgai. We determined 16S-23S rDNA internal transcribed spacer (ITS) sequences of 60 strains in the genus Mycobacterium representing 13 species (M. avium, M. conspicuum, M. gastri, M. genavense, M. kansasii, M. malmoense, M. marinum, M. shimoidei, M. simiae, M. szulgai, M. triplex, M. ulcerans, and M. xenopi). An alignment of these sequences together with additional sequences available in the EMBL database (for M. intracellulare, M. phlei, M. smegmatis, and M. tuberculosis) was established according to primary- and secondary-structure similarities. Comparative sequence analysis applying different treeing methods grouped the strains into species-specific clusters with low sequence divergence between strains belonging to the same species (0 to 2%). The ITS-based tree topology only partially correlated to that based on 16S rDNA, but the main branching orders were preserved, notably, the division of fast-growing from slowly growing mycobacteria, separate branching for M. simiae, M. genavense, and M. triplex, and distinct branches for M. xenopi and M. shimoidei. Comparisons of M. gastri with M. kansasii and M. malmoense with M. szulgai revealed ITS sequence similarities of 93 and 88%, respectively. M. marinum and M. ulcerans possessed identical ITS sequences. Our results show that ITS sequencing represents a supplement to 16S rRNA gene sequences for the differentiation of closely related species. Slowly growing mycobacteria show a high sequence variation in the ITS; this variation has the potential to be used for the development of probes as a rapid approach to mycobacterial identification.

BACKGROUND: Scale-up of insecticide-based interventions has averted more than 500 million malaria cases since 2000. Increasing insecticide resistance could herald a rebound in disease and mortality. We aimed to investigate whether insecticide resistance was associated with loss of effectiveness of long-lasting insecticidal nets and increased malaria disease burden. METHODS: This WHO-coordinated, prospective, observational cohort study was done at 279 clusters (villages or groups of villages in which phenotypic resistance was measurable) in Benin, Cameroon, India, Kenya, and Sudan. Pyrethroid long-lasting insecticidal nets were the principal form of malaria vector control in all study areas; in Sudan this approach was supplemented by indoor residual spraying. Cohorts of children from randomly selected households in each cluster were recruited and followed up by community health workers to measure incidence of clinical malaria and prevalence of infection. Mosquitoes were assessed for susceptibility to pyrethroids using the standard WHO bioassay test. Country-specific results were combined using meta-analysis. FINDINGS: Between June 2, 2012, and Nov 4, 2016, 40 000 children were enrolled and assessed for clinical incidence during 1·4 million follow-up visits. 80 000 mosquitoes were assessed for insecticide resistance. Long-lasting insecticidal net users had lower infection prevalence (adjusted odds ratio [OR] 0·63, 95% CI 0·51-0·78) and disease incidence (adjusted rate ratio [RR] 0·62, 0·41-0·94) than did non-users across a range of resistance levels. We found no evidence of an association between insecticide resistance and infection prevalence (adjusted OR 0·86, 0·70-1·06) or incidence (adjusted RR 0·89, 0·72-1·10). Users of nets, although significantly better protected than non-users, were nevertheless subject to high malaria infection risk (ranging from an average incidence in net users of 0·023, [95% CI 0·016-0·033] per person-year in India, to 0·80 [0·65-0·97] per person year in Kenya; and an average infection prevalence in net users of 0·8% [0·5-1·3] in India to an average infection prevalence of 50·8% [43·4-58·2] in Benin). INTERPRETATION: Irrespective of resistance, populations in malaria endemic areas should continue to use long-lasting insecticidal nets to reduce their risk of infection. As nets provide only partial protection, the development of additional vector control tools should be prioritised to reduce the unacceptably high malaria burden. FUNDING: Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.

BACKGROUND: Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies has been limited by a lack of standardization of diagnostic methods. OBJECTIVES: To develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. METHODS: Consensus diagnostic criteria were developed through a Delphi study with international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of the available literature and the opinion of an expanded group of international experts to develop detailed, evidence-based definitions and diagnostic methods. RESULTS: The 2020 International Alliance for the Control of Scabies (IACS) Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed scabies (level A) requires direct visualization of the mite or its products. Clinical scabies (level B) and suspected scabies (level C) rely on clinical assessment of signs and symptoms. Evidence-based, consensus methods for microscopy, visualization and clinical symptoms and signs were developed, along with a media library. CONCLUSIONS: The 2020 IACS Criteria represent a pragmatic yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardization for scabies diagnosis. Validation studies, development of training materials and development of survey methods are now required. What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical. Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common. These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts. The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings. Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis.