United States Agency for International Development

IMPORTANCE: Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood. OBJECTIVE: To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking. DESIGN, SETTING, AND PARTICIPANTS: We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015. EXPOSURES: Leisure-time physical activity of a moderate to vigorous intensity. MAIN OUTCOMES AND MEASURES: Incident cancer during follow-up. RESULTS: A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers. CONCLUSIONS AND RELEVANCE: Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.

countries can be reduced by 2035 through inexpensive population-based and clinical interventions.Fiscal policies are an especially promising lever for reducing this burden. Opportunities:• National governments can curb NCDs and raise signifi cant revenue by heavily taxing tobacco and other harmful substances, and they can redirect fi nances towards NCD control by reducing subsidies on items such as fossil fuels.Investment in strengthening health systems to deliver packages of costeff ective clinical interventions for NCDs and injuries is another important national opportunity.• International action should focus on provision of technical assistance on fi scal policies, regional cooperation on tobacco, and funding of population, policy, and implementation research on scaling-up of interventions for NCDs and injuries.Progressive universalism, a pathway to universal health coverage (UHC), is an effi cient way to achieve health and fi nancial protectionThe Commission endorses two pro-poor pathways to achieving UHC within a generation.In the fi rst, publicly fi nanced insurance would cover essential health-care interventions to achieve convergence and tackle NCDs and injuries.This pathway would directly benefi t the poor because they are disproportionately aff ected by these problems.The second pathway provides a larger benefi t package, funded through a range of fi nancing mechanisms, with poor people exempted from payments.Opportunities:• For national governments, progressive universalism would yield high health gains per dollar spent and poor people would gain the most in terms of health and fi nancial protection.• The international community can best support countries to implement progressive universal health coverage by fi nancing population, policy, and imple mentation research, such as on the mechanics of designing and implementing evolution of the benefi ts package as the resource envelope for public fi nance grows.Our report points to the possibility of achieving dramatic gains in global health by 2035 through a grand con vergence around infectious, child, and maternal mortality; major reductions in the incidence and consequences of NCDs and injuries; and the promise of universal health coverage.Good reasons exist to be optimistic about seeing the global health landscape utterly transformed in this way within our lifetimes.For the background papers see http://globalhealth2035.org Panel 2: Social and intersectoral determinants and consequences of better healthThree key WHO publications have advanced our understanding of these relations: • The 1999 World Health Report (WHR), the fi rst WHR issued by WHO Director General Gro Harlem Brundtland, estimated that half of the health improvements between 1960 and 1990 in low-income and middle-income countries were from changes in two social determinants: income and education.7 The report noted that these determinants aff ect health through consequences such as poor nutrition, sanitation, and other risk factors for ill health.Nevertheless, WHR 1999 argued that the health community could have the greatest eff ect on health by focusing on the health sector, including health systems strengthening, rather than by taking action outside this sector.• The 2001 report of the Commission on Macroeconomics and Health, chaired by Jeff rey Sachs, emphasised the importance of investment not only in the health sector but also in education, water, sanitation, and agriculture, to reduce poverty.8 By quantifying both the substantial economic consequences of better health and the costs of achieving it, the report had a hugely important role in informed advocacy for the health sector.• The Commission on Social Determinants of Health, chaired by Michael Marmot, was established by WHO in 2005 to lay out evidence for how to promote health equity through sound social and economic policies and to foster a global movement towards its achievement.9 The Commission made three broad recommendations: improve daily conditions; take "far-reaching and systematic action" to improve the distribution of resources to ensure "fair fi nancing, corporate social responsibility, gender equity and better governance"; and improve data collection for better measurement of health inequities and monitor the eff ect of interventions in improving these inequities.

OBJECTIVE: There is limited evidence on whether growing mobile phone availability in sub-Saharan Africa can be used to promote high adherence to antiretroviral therapy (ART). This study tested the efficacy of short message service (SMS) reminders on adherence to ART among patients attending a rural clinic in Kenya. DESIGN: A randomized controlled trial of four SMS reminder interventions with 48 weeks of follow-up. METHODS: Four hundred and thirty-one adult patients who had initiated ART within 3 months were enrolled and randomly assigned to a control group or one of the four intervention groups. Participants in the intervention groups received SMS reminders that were either short or long and sent at a daily or weekly frequency. Adherence was measured using the medication event monitoring system. The primary outcome was whether adherence exceeded 90% during each 12-week period of analysis and the 48-week study period. The secondary outcome was whether there were treatment interruptions lasting at least 48 h. RESULTS: In intention-to-treat analysis, 53% of participants receiving weekly SMS reminders achieved adherence of at least 90% during the 48 weeks of the study, compared with 40% of participants in the control group (P = 0.03). Participants in groups receiving weekly reminders were also significantly less likely to experience treatment interruptions exceeding 48 h during the 48-week follow-up period than participants in the control group (81 vs. 90%, P = 0.03). CONCLUSION: These results suggest that SMS reminders may be an important tool to achieve optimal treatment response in resource-limited settings.

Plant disease outbreaks are increasing and threaten food security for the vulnerable in many areas of the world. Now a global human pandemic is threatening the health of millions on our planet. A stable, nutritious food supply will be needed to lift people out of poverty and improve health outcomes. Plant diseases, both endemic and recently emerging, are spreading and exacerbated by climate change, transmission with global food trade networks, pathogen spillover, and evolution of new pathogen lineages. In order to tackle these grand challenges, a new set of tools that include disease surveillance and improved detection technologies including pathogen sensors and predictive modeling and data analytics are needed to prevent future outbreaks. Herein, we describe an integrated research agenda that could help mitigate future plant disease pandemics.

BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success. METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030. FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone. INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030. FUNDING: Bill & Melinda Gates Foundation, US Agency for International Development.

This paper describes an action framework for countries with low tuberculosis (TB) incidence (<100 TB cases per million population) that are striving for TB elimination. The framework sets out priority interventions required for these countries to progress first towards "pre-elimination" (<10 cases per million) and eventually the elimination of TB as a public health problem (less than one case per million). TB epidemiology in most low-incidence countries is characterised by a low rate of transmission in the general population, occasional outbreaks, a majority of TB cases generated from progression of latent TB infection (LTBI) rather than local transmission, concentration to certain vulnerable and hard-to-reach risk groups, and challenges posed by cross-border migration. Common health system challenges are that political commitment, funding, clinical expertise and general awareness of TB diminishes as TB incidence falls. The framework presents a tailored response to these challenges, grouped into eight priority action areas: 1) ensure political commitment, funding and stewardship for planning and essential services; 2) address the most vulnerable and hard-to-reach groups; 3) address special needs of migrants and cross-border issues; 4) undertake screening for active TB and LTBI in TB contacts and selected high-risk groups, and provide appropriate treatment; 5) optimise the prevention and care of drug-resistant TB; 6) ensure continued surveillance, programme monitoring and evaluation and case-based data management; 7) invest in research and new tools; and 8) support global TB prevention, care and control. The overall approach needs to be multisectorial, focusing on equitable access to high-quality diagnosis and care, and on addressing the social determinants of TB. Because of increasing globalisation and population mobility, the response needs to have both national and global dimensions.

Permanganate oxidizable C (POXC; i.e., active C) is a relatively new method that can quantify labile soil C rapidly and inexpensively. Despite limited reports of positive correlations with particulate organic C (POC), microbial biomass C (MBC), and other soil C fractions, little is known about what soil fractions POXC most closely reflects. We measured POXC across a wide range of soil types, ecosystems, and geographic areas (12 studies, 53 total sites, n = 1379) to: (i) determine the relationship between POXC and POC, MBC and soil organic C (SOC) fractions, and (ii) determine the relative sensitivity of POXC as a labile soil C metric across a range of environmental and management conditions. Permanganate oxidizable C was significantly related to POC, MBC, and SOC, and these relationships were strongest when data were analyzed by individual studies. Permanganate oxidizable C was more closely related to smaller-sized (53–250 μm) than larger POC fractions (250–2000 μm), and more closely related to heavier (>1.7 g cm−3) than lighter POC fractions, indicating that it reflects a relatively processed pool of labile soil C. Compared with POC, MBC, or SOC, POXC demonstrated greater sensitivity to changes in management or environmental variation in 42% of the significant experimental factors examined across the 12 studies. Our analysis demonstrates the usefulness of POXC in quickly and inexpensively assessing changes in the labile soil C pool.

Transposable genetic elements (TEs) comprise a vast array of DNA sequences, all having the ability to move to new sites in genomes either directly by a cut-and-paste mechanism (transposons) or indirectly through an RNA intermediate (retrotransposons). First discovered in maize plants by the

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.

This systematic review of 58 observational studies identified hypothetical causal mechanisms explaining the effects of short and long intervals between pregnancies on maternal, perinatal, infant, and child health, and critically examined the scientific evidence for each causal mechanism hypothesized. The following hypothetical causal mechanisms for explaining the association between short intervals and adverse outcomes were identified: maternal nutritional depletion, folate depletion, cervical insufficiency, vertical transmission of infections, suboptimal lactation related to breastfeeding-pregnancy overlap, sibling competition, transmission of infectious diseases among siblings, incomplete healing of uterine scar from previous cesarean delivery, and abnormal remodeling of endometrial blood vessels. Women's physiological regression is the only hypothetical causal mechanism that has been proposed to explain the association between long intervals and adverse outcomes. We found growing evidence supporting most of these hypotheses.

The ongoing pandemic caused by SARS-CoV-2, the causal agent of the acute respiratory distress syndrome COVID-19, is placing unprecedented stress on healthcare systems and societies as a whole. The rapid spread of the virus in the absence of targeted therapies or a vaccine, is forcing countries to respond with strong preventative measures ranging from mitigation to containment. In extreme cases, quarantines are being imposed, limiting mobility to varying degrees.

Voluntary family planning brings transformational benefits to women, families, communities, and countries. Investing in family planning is a development “best buy” that can accelerate achievement across the 5 Sustainable Development Goal themes of People, Planet, Prosperity, Peace, and Partnership.

BACKGROUND: Effective national and global HIV responses require a significant expansion of HIV testing and counselling (HTC) to expand access to prevention and care. Facility-based HTC, while essential, is unlikely to meet national and global targets on its own. This article systematically reviews the evidence for community-based HTC. METHODS AND FINDINGS: PubMed was searched on 4 March 2013, clinical trial registries were searched on 3 September 2012, and Embase and the World Health Organization Global Index Medicus were searched on 10 April 2012 for studies including community-based HTC (i.e., HTC outside of health facilities). Randomised controlled trials, and observational studies were eligible if they included a community-based testing approach and reported one or more of the following outcomes: uptake, proportion receiving their first HIV test, CD4 value at diagnosis, linkage to care, HIV positivity rate, HTC coverage, HIV incidence, or cost per person tested (outcomes are defined fully in the text). The following community-based HTC approaches were reviewed: (1) door-to-door testing (systematically offering HTC to homes in a catchment area), (2) mobile testing for the general population (offering HTC via a mobile HTC service), (3) index testing (offering HTC to household members of people with HIV and persons who may have been exposed to HIV), (4) mobile testing for men who have sex with men, (5) mobile testing for people who inject drugs, (6) mobile testing for female sex workers, (7) mobile testing for adolescents, (8) self-testing, (9) workplace HTC, (10) church-based HTC, and (11) school-based HTC. The Newcastle-Ottawa Quality Assessment Scale and the Cochrane Collaboration's "risk of bias" tool were used to assess the risk of bias in studies with a comparator arm included in pooled estimates. 117 studies, including 864,651 participants completing HTC, met the inclusion criteria. The percentage of people offered community-based HTC who accepted HTC was as follows: index testing, 88% of 12,052 participants; self-testing, 87% of 1,839 participants; mobile testing, 87% of 79,475 participants; door-to-door testing, 80% of 555,267 participants; workplace testing, 67% of 62,406 participants; and school-based testing, 62% of 2,593 participants. Mobile HTC uptake among key populations (men who have sex with men, people who inject drugs, female sex workers, and adolescents) ranged from 9% to 100% (among 41,110 participants across studies), with heterogeneity related to how testing was offered. Community-based approaches increased HTC uptake (relative risk [RR] 10.65, 95% confidence interval [CI] 6.27-18.08), the proportion of first-time testers (RR 1.23, 95% CI 1.06-1.42), and the proportion of participants with CD4 counts above 350 cells/µl (RR 1.42, 95% CI 1.16-1.74), and obtained a lower positivity rate (RR 0.59, 95% CI 0.37-0.96), relative to facility-based approaches. 80% (95% CI 75%-85%) of 5,832 community-based HTC participants obtained a CD4 measurement following HIV diagnosis, and 73% (95% CI 61%-85%) of 527 community-based HTC participants initiated antiretroviral therapy following a CD4 measurement indicating eligibility. The data on linking participants without HIV to prevention services were limited. In low- and middle-income countries, the cost per person tested ranged from US$2-US$126. At the population level, community-based HTC increased HTC coverage (RR 7.07, 95% CI 3.52-14.22) and reduced HIV incidence (RR 0.86, 95% CI 0.73-1.02), although the incidence reduction lacked statistical significance. No studies reported any harm arising as a result of having been tested. CONCLUSIONS: Community-based HTC achieved high rates of HTC uptake, reached people with high CD4 counts, and linked people to care. It also obtained a lower HIV positivity rate relative to facility-based approaches. Further research is needed to further improve acceptability of community-based HTC for key populations. HIV programmes should offer community-based HTC linked to prevention and care, in addition to facility-based HTC, to support increased access to HIV prevention, care, and treatment. REVIEW REGISTRATION: International Prospective Register of Systematic Reviews CRD42012002554 Please see later in the article for the Editors' Summary.

Demographic research frequently reports consistent and significant associations between formal educational attainment and a range of health risks such as smoking, drug abuse, and accidents, as well as the contraction of many diseases, and health outcomes such as mortality—almost all indicating the same conclusion: better-educated individuals are healthier and live longer. Despite the substantial reporting of a robust education effect, there is inadequate appreciation of its independent influence and role as a causal agent. To address the effect of education on health in general, three contributions are provided: 1) a macro-level summary of the dimensions of the worldwide educational revolution and a reassessment of its causal role in the health of individuals and in the demographic health transition are carried out; 2) a meta-analysis of methodologically sophisticated studies of the effect of educational attainment on all-cause mortality is conducted to establish the independence and robustness of the education effect on health; and 3) a schooling-cognition hypothesis about the influence of education as a powerful determinant of health is developed in light of new multidisciplinary cognitive research.

The benefits of new methods of prevention of HIV could be jeopardised if they are not accompanied by efforts to change risky behaviour

The recently updated World Health Organization (WHO) consolidated guidelines on the use of antiretroviral therapy (ART) recommending to “treat all” mark a paradigm shift in the delivery of HIV treatment: from who is eligible and when to start ART, to how to provide client-centred and high-quality care to all people living with HIV (PLHIV). As part of this shift, the new guidance includes service delivery recommendations based on a “differentiated care framework” [1]. Yet, despite the increased global attention paid to differentiated care [2–4], the concept is not well defined. There is broad agreement that a “one-size-fits-all” model of HIV services will not succeed in providing sustainable access to ART and support services for the 37 million PLHIV today. Instead, health systems will need to both accelerate ART initiation and support retention and viral suppression, which requires adapting HIV services to specific client populations and contexts [5]. Past discussions have looked at differentiated care through a health system's lens – focusing on what aspects of care are needed, how often they are needed, where care should be delivered and who will provide it [6]. An approach to HIV testing, care and treatment that distinguishes client groups according to broad definitions, however, is more likely to succeed. Differentiated care is a client-centred approach that simplifies and adapts HIV services across the cascade, in ways that both serve the needs of PLHIV better and reduce unnecessary burdens on the health system. Differentiated care incorporates concepts such as simplification, task shifting and decentralization, which have also been called “community-based care, optimized care, patient-centred/focussed care, needs-based care [and] tiered care” [6]. The health system implications of this client-centred approach are clear: when a health system adopts a more responsive model of care, tailored to the needs of various groups of PLHIV, it can allocate resources more effectively, provide better access for underserved populations and deliver care in ways to improve quality of care and life. While differentiated approaches are often more cost-effective in an environment where funding for HIV is under threat, it is critical to ensure that the primary focus for differentiating care remains to improve quality rather than to prop up a misleading “more with less” agenda. Well-known models of differentiated care have focused on ART delivery to clients who are clinically stable and have largely been implemented in high-prevalence countries in sub-Saharan Africa. Examples include client-managed groups (e.g. community adherence groups in Mozambique [7]), health care worker-managed groups (e.g. adherence clubs in South Africa [8]), facility-based individual delivery (e.g. “fast track” ART refills in Malawi [9]) and out-of-facility individual delivery (e.g. community drug distribution points in Uganda [10]). To succeed, however, differentiated care must not be limited to stable client models or solely to ART delivery. Policymakers and implementers should “differentiate” care for defined groups according to three elements as defined in Figure 1: (1) clinical characteristics; (2) sub-population; and (3) context [11]. Examples of differentiated care can be found across the cascade and the three elements including expanded PrEP access for sex workers in South Africa [12], a “one-window” approach for people who use drugs in Ukraine [13], targeted peer-led testing of key populations in Thailand [14] and in low-prevalence settings with stable client delivery models in Myanmar [15]. Beyond stable clients: service delivery should be differentiated considering three elements [11]. Differentiated care is also a rights-based approach that can act as a modality of stigma and discrimination reduction irrespective of whether or not those rights are formally recognized in laws [16]. By considering the context of the client and health system, differentiated care can help to address policy barriers related to who can dispense versus distribute ART and who can conduct HIV testing. In addition, implementation, particularly at the national level, affords significant opportunities to confront legal and structural barriers that prevent underserved client groups from accessing services [17]. While national policies endorsing differentiated care are necessary for scale-up of HIV services, successful implementation will be dependent on an enabling environment inclusive of a robust drug supply (including fast tracked drug pick-ups and 3–6 month ART refills); access to laboratory monitoring, in particular viral load; a reliable monitoring and evaluation system; and recognition of lay workers. Achieving and sustaining these high-quality services also requires an empowered PLHIV community and civil society. Together, these bodies can advocate and create demand for services that are best tailored to the needs of clients in a given context. The release of the new WHO guidelines add to the momentum around differentiated care, as evidenced by PEPFAR's Technical Considerations and the Global Fund's toolkit [3, 4] and provide opportunities to reimagine, reorganize and scale up client-centred approaches to HIV service delivery at the national level [1]. The inclusion of differentiated care also catalyses long-standing efforts of rights and community advocates to provide holistic and supportive care, particularly to underserved client groups [18]. Thirty-seven million PLHIV worldwide need lifelong ART. To achieve this, countries must adopt and adapt existing models of differentiated care to meet both the diverse needs of PLHIV and the capacity and constraints of their health systems. To ensure sustainability, successful programmes must be supported by national policies and be adequately funded. The impact of the scale-up of differentiated care models should be evaluated with clear indicators, including quality and outcomes of care, client and health care worker satisfaction, and costs to both the client and the health system. As the models are implemented and improved through analysis of programme data, quality improvement mechanisms and implementation research, stakeholders can work together to address the priority challenges that arise. Differentiated care is not just about stable clients – but providing quality care from prevention to suppression, including for clients who are unstable or have advanced disease. The global HIV community must seize the opportunity to reimagine service delivery where focus is placed on the quality of services that PLHIV receive. As has been demonstrated throughout the history of the HIV response, lessons learned from HIV can inform and improve care and service delivery across a range of health issues and vice versa. Hence, leveraging the concept of differentiated care beyond HIV to other chronic diseases for all clients will strengthen health systems and contribute to reaching Sustainable Development Goal 3 – “good health and well-being” [19]. To reach that goal, ministries of health, implementing partners, donors, civil society and communities of PLHIV will first need to unite around a differentiated care concept that puts people at the centre of services. The authors would like to thank Kevin Osborne, Owen Ryan and Mark Aurigemma for their comments. None of the authors have any competing interests to declare. The concept for this was developed by HB, MD, PE, TE, RF, NF, AG and IZ. HB and AG wrote the first draft. All authors contributed and approved the final version. The views and opinions expressed here are solely those of the authors in their private capacity. The content in this document are those of the authors and do not necessarily reflect the views of the United States Agency for International Development or the United States Government.

Continuous exposure of cells to hormonal agonists often causes a rapid waning of the stimulated response. This desensitization effect has been extensively studied in the beta-adrenergic receptor system, and attributed largely to the rapid phosphorylation of the receptor by two kinases. Over a similar time frame (seconds to minutes), agonists also trigger a selective loss in the capacity of receptors to bind hydrophilic but not hydrophobic ligands, a phenomenon termed sequestration. There is some evidence suggesting that sequestration represents the rapid internalization of receptors, but the functional significance of sequestration has remained unclear. Upon the removal of agonist, both desensitization and sequestration are readily reversed with similar kinetics (t1/2 approximately 3 min for both). To investigate the possibility that receptor sequestration is involved in this resensitization of the adenylyl cyclase response, we applied two distinct approaches to block receptor sequestration: by pretreating cells with sucrose and by creating a sequestration-defective beta 2-adrenergic receptor by site-specific mutagenesis. Both approaches effectively disabled receptor sequestration, with little effect on adenylyl cyclase stimulation or on desensitization. However, in both cases, no recovery from desensitization was apparent even 20 min after the removal of agonist. Similarly, pretreating cells with concanavalin A almost completely blocked receptor sequestration and resensitization but only partially inhibited other receptor functions. Our results therefore suggest that sequestration of beta 2-adrenergic receptors is a mechanism involved in reactivating and recycling desensitized receptors.

Abstract Different chemical, physical, and biological properties of a soil interact in complex ways that determine its potential fitness or capacity to produce healthy and nutritious crops. The integration of these properties andine resulting level of productivity often is referred to as “soil quality.” Soil quality can be defined as an inherent attribute of a soil that is inferred from its specific characteristics and observations (e.g., compactability, erodibility, and fertility). The term also refers to the soil's structural integrity, which imparts resistance to erosion, and to the loss of plant nutrients and organic matter. Soil quality often is related to soil degradation, which can be defined as the time rate of change in soil quality. Soil quality should not be limited to soil productivity, but should encompass environmental quality, human and animal health, and food safety and quality. There is inadequate reliable information on how changes in soil quality directly affect food quality, or indirectly affect human and animal health. In characterizing soil quality, biological properties have received less emphasis than chemical and physical properties, because their effects are difficult to measure, predict, or quantify. Improved soil quality often is indicated by increased infiltration, aeration, macropores, aggregate size, aggregate stability, and soil organic matter, and by decreased bulk density, soil resistance, erosion, and nutrient runoff. These are useful, but future research should seek to identify and quantify reliable and meaningful biological/ecological indicators of soil quality, such as total species diversity or genetic diversity of beneficial soil microorganisms, insects, and animals. Because these biological/ecological indexes of soil quality are dynamic, they will require effective monitoring and assessment programs to develop appropriate databases for research and technology transfer. We need to know how such indexes are affected by management inputs, whether they can serve as early warning indicators of soil degradation, and how they relate to the sustainability of agricultural systems.

Populations affected by armed conflict have experienced severe public health consequences mediated by population displacement, food scarcity, and the collapse of basic health services, giving rise to the term complex humanitarian emergencies. These public health effects have been most severe in underdeveloped countries in Africa, Asia, and Latin America. Refugees and internally displaced persons have experienced high mortality rates during the period immediately following their migration. In Africa, crude mortality rates have been as high as 80 times baseline rates. The most common causes of death have been diarrheal diseases, measles, acute respiratory infections, and malaria. High prevalences of acute malnutrition have contributed to high case fatality rates. In conflict-affected European countries, such as the former Yugoslavia, Georgia, Azerbaijan, and Chechnya, war-related injuries have been the most common cause of death among civilian populations; however, increased incidence of communicable diseases, neonatal health problems, and nutritional deficiencies (especially among the elderly) have been documented. The most effective measures to prevent mortality and morbidity in complex emergencies include protection from violence; the provision of adequate food rations, clean water and sanitation; diarrheal disease control; measles immunization; maternal and child health care, including the case management of common endemic communicable diseases; and selective feeding programs, when indicated.

___Key messages___ The Commission recommends five priority investments to achieve a tuberculosis-free world within a generation. These investments are designed to fulfil the mandate of the UN High Level Meeting on tuberculosis. In addition, they answer the question of how countries with high-burden tuberculosis and their development partners should target their future investments to ensure that ending tuberculosis is achievable. __Invest first to ensure that high quality rapid diagnostics and treatment are provided to all individuals receiving care for tuberculosis, wherever they seek care__ This priority includes rapid drug susceptibility testing and second-line treatment for resistant forms of tuberculosis. Achieving universal, high-quality person-centred and family-centred care—including sustained improvement in the performance of private sector providers—usually should be the top policy and budget priority. __Reach people and populations at high risk for tuberculosis (such as household and other close contacts of people with tuberculosis, and people with HIV) and bring them into care__ Active case-finding and treatment in high-risk populations demands adequate resources to reach and care for these populations. At the same time, reaching certain high-risk populations, such as people co-infected with tuberculosis and HIV, for tuberculosis preventive therapy is essential to achieve epidemiologic control. Once high-risk populations have access to affordable, high-quality diagnostic, treatment and preventive services, invest in identifying tuberculosis cases in the general population, primarily by strengthening the capacity to deliver health services and move toward universal health coverage. __Increase investment to accelerate tuberculosis research and development and bring new diagnostics, therapeutic strategies, and vaccines to clinical practice to quickly end the pandemic__ Strong advocacy with science ministries and research-oriented pharmaceutical companies is crucial, including ministries and companies in middle-income countries, to highlight the importance of investing in new tools. Financing the early uptake of new products will provide important confidence signals to product developers. __Make investment in tuberculosis programmes a shared responsibility, increasing development assistance for tuberculosis according to the financial needs of individual low-income and middle-income countries__ As countries successfully mobilise more domestic resources towards tuberculosis programmes, external assistance to middle-income countries should address the following priorities: reduce the spread of drug-resistant tuberculosis in all affected low-income and middle-income countries; facilitate market-shaping activities to enable access to high quality drugs and diagnostics for high-burden countries; and finance tuberculosis research and development, including product development as well as population, policy, and implementation research that will provide lessons and international sharing of best practices. __Hold countries and key stakeholders accountable for progress made towards ending tuberculosis__ Accountability entails establishing independent, multisectoral processes, such as national tuberculosis report cards, to ensure that all stakeholders carry out their responsibilities to contribute to ending the pandemic. Accountability mechanisms should not only assess progress, but also guarantee that Heads of Governments, national tuberculosis programmes, and even regional and site-level clinics, as well as key non-governmental organisations, take the necessary corrective actions to remove obstacles to ending tuberculosis.