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Abstract Background Integrating trees into agricultural landscapes can provide climate mitigation and improves soil fertility, biodiversity habitat, water quality, water flow, and human health, but these benefits must be achieved without reducing agriculture yields. Prior estimates of carbon dioxide (CO2) removal potential from increasing tree cover in agriculture assumed a moderate level of woody biomass can be integrated without reducing agricultural production. Instead, we used a Delphi expert elicitation to estimate maximum tree covers for 53 regional cropping and grazing system categories while safeguarding agricultural yields. Comparing these values to baselines and applying spatially explicit tree carbon accumulation rates, we develop global maps of the additional CO2 removal potential of Tree Cover in Agriculture. We present here the first global spatially explicit datasets calibrated to regional grazing and croplands, estimating opportunities to increase tree cover without reducing yields, therefore avoiding a major cost barrier to restoration: the opportunity cost of CO2 removal at the expense of agriculture yields. Results The global estimated maximum technical CO2 removal potential is split between croplands (1.86 PgCO2 yr− 1) and grazing lands (1.45 PgCO2 yr− 1), with large variances. Tropical/subtropical biomes account for 54% of cropland (2.82 MgCO2 ha− 1 yr− 1, SD = 0.45) and 73% of grazing land potential (1.54 MgCO2 ha− 1 yr− 1, SD = 0.47). Potentials seem to be driven by two characteristics: the opportunity for increase in tree cover and bioclimatic factors affecting CO2 removal rates. Conclusions We find that increasing tree cover in 2.6 billion hectares of agricultural landscapes may remove up to 3.3 billion tons of CO2 per year – more than the global annual emissions from cars. These Natural Climate Solutions could achieve the Bonn Challenge and add 793 million trees to agricultural landscapes. This is significant for global climate mitigation efforts because it represents a large, relatively inexpensive, additional CO2 removal opportunity that works within agricultural landscapes and has low economic and social barriers to rapid global scaling. There is an urgent need for policy and incentive systems to encourage the adoption of these practices.

Abstract Natural climate solutions can mitigate climate change in the near-term, during a climate-critical window. Yet, persistent misunderstandings about what constitutes a natural climate solution generate unnecessary confusion and controversy, thereby delaying critical mitigation action. Based on a review of scientific literature and best practices, we distill five foundational principles of natural climate solutions (nature-based, sustainable, climate-additional, measurable, and equitable) and fifteen operational principles for practical implementation. By adhering to these principles, practitioners can activate effective and durable natural climate solutions, enabling the rapid and wide-scale adoption necessary to meaningfully contribute to climate change mitigation.

Background: In 2017, the WHO recommended the use of digital technologies, such as medication monitors and video observed treatment (VOT), for directly observed treatment (DOT) of drug-susceptible TB. The WHO's 2020 guidelines extended these recommendations to multidrug-resistant tuberculosis (MDR-TB), based on low evidence. The impact of COVID on health systems and patients underscored the need to use digital technologies in the management of MDR-TB., Methods: A decision-tree model was developed to explore the costs of several potential DOT alternatives: VOT, 99DOTS (Directly-observed Treatment, Short-course) and family-observed DOT. Assuming a 9-month, all-oral regimen (as evaluated within the STREAM trial), we constructed base-case cost models for the standard-of-care DOTs in Ethiopia, India, and Uganda, as well as for the three alternative DOT approaches. The models were populated with STREAM Stage 2 clinical trial outcome and cost data, supplemented with market prices data for the digital DOT strategies. Sensitivity analyses were conducted on key parameters., Results: Modelling suggested that the standard-of-care DOT approach is the most expensive DOT strategy from a societal perspective in all three countries evaluated (Ethiopia, India, Uganda), with considerable direct- and indirect-costs incurred by patients. The second most expensive DOT approach is VOT, with high health-system costs, largely caused by up-front technology expenditure. Each of VOT, 99DOTS and family-observed DOT would reduce by more than 90% patients' direct and indirect costs compared to standard of care DOT. Results were robust to the sensitivity analyses., Conclusions: While data on the costs and efficacy of alternative DOT approaches in the context of shorter MDR-TB treatment is limited, our modelling suggests alternative DOT approaches can significantly reduce patient costs in all three countries. Health system costs are higher for VOT and lower for 99DOTS and family-observed therapy when compared to standard of care DOT, as low smartphone penetration and internet availability requires the VOT health system to fund the cost of making them available to patients., (© 2023. The Author(s).)

Background: The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens., Methods: STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631., Findings: 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia, $1900 in India, $3950 in Moldova, and $7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia, $3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from $1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India., Interpretation: At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable., Funding: USAID and Janssen Research & Development., Competing Interests: Declaration of interests LR reports consulting fees from GSK (paid to institution) and support for attending trial-related meetings from Janssen Research & Development and the US Agency for International Development (USAID; paid to institution). JJM reports support for attending meetings or travel from the Liverpool School of Tropical Medicine. EMT reports consulting fees from GSK (paid to institution) and support for attending meetings from USAID (paid to institution). MM, PB, RD, GN, AKBh, BK, SKM, AJN, GB, IDR, and EW report support for attending trial-related meetings from Janssen Research & Development and USAID (paid to institution). ET reports support for attending meetings from USAID (paid to institution). SBS reports a research grant on tuberculosis research (paid to institution) from the UK Foreign & Commonwealth Development Office, support for attending trial-related meetings from Janssen Research & Development and USAID (paid to institution), and is co-chair of the Scientific Working Group on Implementation Research for the Tropical Disease Research Foundation (unpaid). All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Design and implementation of multi-country clinical trials for multidrug-resistant tuberculosis (MDR-TB) are complex for several reasons, including trial duration, varying levels of experience and infrastructure across settings, and different regulatory requirements. STREAM was an MDR-TB clinical trial that recruited over 1000 participants. We documented challenges and best practices/lessons learned from the site perspective to improve implementation of future trials., Methods: We conducted a voluntary survey of trial staff at all sites to obtain information on challenges encountered and best practices/lessons learned from implementation of the STREAM trial. Respondents were asked to identify substantive aspects of trial implementation from a list that included: trial administration, laboratory strengthening/infrastructure, pharmacy and supply chain management, community engagement, regulatory and ethics requirements, health economics, and other (respondent designated) about which a practical guide would be useful to improve future trial implementation. For each aspect of trial implementation selected, respondents were asked to report challenges and best practices/lessons learned during STREAM. Lastly, respondents were asked to list up to three things they would do differently when implementing future trials. Summary statistics were generated for quantitative data and thematic analysis was undertaken for qualitative data., Results: Of 67 responses received from 13 of 15 sites, 47 (70%) were included in the analyses, after excluding duplicate or incomplete responses. Approximately half the respondents were investigators or trial coordinators. The top three aspects of trial implementation identified for a best practices/lessons learned practical guide to improve future trial implementation were: trial administration, community engagement, and laboratory strengthening/infrastructure. For both challenges and best practices/lessons learned, three common themes were identified across different aspects of trial implementation. Investment in capacity building and ongoing monitoring; investment in infrastructure and well-designed trial processes; and communication and coordination between staff and meaningful engagement of stakeholders were all thought to be critical to successful trial implementation., Conclusions: Existing practices for clinical trial implementation should be reevaluated. Sponsors should consider the local context and the need to increase upfront investment in the cross-cutting thematic areas identified to improve trial implementation., (© 2023. The Author(s).)

Background: The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen., Methods: We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631., Findings: Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss., Interpretation: Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss., Funding: USAID and Janssen Research & Development., Competing Interests: Declaration of interests SBS received a grant from the UK Foreign & Commonwealth Development Office for tuberculosis research through his institution. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial's design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally.Trial registration: ISRCTN ISRCTN18148631 . Registered 10 February 2016., (© 2022. The Author(s).)

HIV/AIDS remains the second most common cause of death in low and middle-income countries (LMICs), and only 34% of eligible patients in Africa received antiretroviral therapy (ART) in 2013. This study investigated the impact of ART decentralization on patient enrollment and retention in rural Malawi. We reviewed electronic medical records of patients registered in the Neno District ART program from August 1, 2006, when ART first became available, through December 31, 2013. We used GPS data to calculate patient-level distance to care, and examined number of annual ART visits and one-year lost to follow-up (LTFU) in HIV care. The number of ART patients in Neno increased from 48 to 3,949 over the decentralization period. Mean travel distance decreased from 7.3 km when ART was only available at the district hospital to 4.7 km when ART was decentralized to 12 primary health facilities. For patients who transferred from centralized care to nearer health facilities, mean travel distance decreased from 9.5 km to 4.7 km. Following a transfer, the proportion of patients achieving the clinic's recommended ≥4 annual visits increased from 89% to 99%. In Cox proportional hazards regression, patients living ≥8 km from a health facility had a greater hazard of being LTFU compared to patients <8 km from a facility (adjusted HR: 1.7; 95% CI: 1.5-1.9). ART decentralization in Neno District was associated with increased ART enrollment, decreased travel distance, and increased retention in care. Increasing access to ART by reducing travel distance is one strategy to achieve the ART coverage and viral suppression objectives of the 90-90-90 UNAIDS targets in rural impoverished areas.

Background: Reliable and representative cause of death (COD) statistics are essential to inform public health policy, respond to emerging health needs, and document progress towards Sustainable Development Goals. However, less than one-third of deaths worldwide are assigned a cause. Civil registration and vital statistics (CRVS) systems in low- and lower-middle-income countries are failing to provide timely, complete and accurate vital statistics, and it will still be some time before they can provide physician-certified COD for every death. Proposals: Verbal autopsy (VA) is a method to ascertain the probable COD and, although imperfect, it is the best alternative in the absence of medical certification. There is extensive experience with VA in research settings but only a few examples of its use on a large scale. Data collection using electronic questionnaires on mobile devices and computer algorithms to analyse responses and estimate probable COD have increased the potential for VA to be routinely applied in CRVS systems. However, a number of CRVS and health system integration issues should be considered in planning, piloting and implementing a system-wide intervention such as VA. These include addressing the multiplicity of stakeholders and sub-systems involved, integration with existing CRVS work processes and information flows, linking VA results to civil registration records, information technology requirements and data quality assurance., Conclusions: Integrating VA within CRVS systems is not simply a technical undertaking. It will have profound system-wide effects that should be carefully considered when planning for an effective implementation. This paper identifies and discusses the major system-level issues and emerging practices, provides a planning checklist of system-level considerations and proposes an overview for how VA can be integrated into routine CRVS systems.

Visual scanning patterns of 6-13-week-old infants are derived from some 50 half-minute assessments in which the infants viewed static geometric figures. Measures include fixation dwell-times, saccade lengths, and the choices and sequences of saccadic targets. From the patterns of change across 3 age periods, it appears that as infants grow older an initial salience-guided scanning increasingly is replaced by volitional control over the choice of saccadic targets. The change tentatively is attributed to neural developments within later stages of the infant visual system.

Ion-spray ionization mass spectrometry with gentle conditions for solvent removal has been reported as a useful tool for detection of high-affinity noncovalent complexes of biological relevance formed in solution. Two main objectives of this study were (i) to find whether other types of electrospray ionization (ESI) sources, e.g. where the solvent is removed with the help of heat (thermally assisted electrospray), could be utilized for detection of noncovalent biological complexes of high and low affinity and (ii) to find whether ESI-MS can be used for detection of the association of bovine serum albumin (BSA) with biologically active peptides. Using a well-defined high-affinity association of FK506 with its binding protein (FKBP) as model system we proved that ESI-MS with thermally assisted interphase can be used for detection of the FK506-FKBP complexes in a similar way as was previously shown for electrospray mass spectrometry (Ganem et al., J. Am. Chem. Soc. 113, 6294 (1991)). In mixtures of BSA with a 9-10 molar excess of biologically active peptides, such as growth hormone releasing factor (GRF), glucagon, bradykinin or insulin in ammonium acetate at pH 7.5, complexes with a ratio of 1:1, 1:2 and in some cases 1:3 were detected. On the other hand, these complexes disappeared upon acidification, pointing to their noncovalent nature.(ABSTRACT TRUNCATED AT 250 WORDS)

A Beckman P/ACE 2050 high-performance capillary electrophoresis (HPCE) instrument has been interfaced with a Vestec electrospray ionization (ESI) mass spectrometer for the analysis of recombinant proteins. Peak resolution is not compromised by coupling HPCE to an ESI mass spectrometer. Recombinant bovine and porcine somatotropins (rbSt and rpSt) were used as model proteins. The standard curve of the capillary zone electrophoresis (CZE) method with UV detection for the determination of rpSt is linear in the range of 7-300 fmol with theoretical plates of approximately 410,000 m-1. The relative standard deviation for the rpSt peak migration time is less than 1%. The multiply-charged ion clusters obtained in the CZE-ESI mass spectrum for a sample of rpSt ranged from mlz 1363.2 (the cluster with 16 charges) to 1982.5 (the cluster with 11 charges). The average molecular weights of 21,812.6 and 21,798.3 for a sample of rbSt and rpSt determined in this study were nearly identical to the theoretical values of 21,812.0 and 21,797.9, respectively. Detection limit of the CZE-ESI mass spectrometer is approximately 100 fmol. The CZE method separated mono- and dideamidated species and monoacetylated compounds while the ESI mass spectrometer detected an analogue and a truncated homologue of rpSt comigrating with the major peak. The presence of mono- and dioxidized homologues was also detected in the major peak of some rbSt and rpSt samples. These data clearly indicated that, individually, both CZE and ESI mass spectrometric methods could not detect all impurities. Coupling of the HPCE Instrument and the ESI mass spectrometer enhances analytical capabilities of both tools for rapid characterization of recombinant proteins.

To clarify the basis for infant differences in rate of visual encoding, the eye movements of a sample of 9 12-week-old infants were recorded throughout an encoding experiment. Results showed that the more slowly encoding infants scanned less extensively over the stimulus, often spent extended intervals in the continuous inspection of one part of the figure, and frequently engaged in prolonged fixations. A second experiment provided comparable scanning data from a sample of 9 2-week-old infants. There were significant age differences in the manner of visual scanning, and the scanning style of the more slowly encoding 12-week-old infants proved to be more like that of the younger infants. Possible explanations for both the between-age and within-age differences are proposed.

The electrospray mass spectra of several standard proteins were recorded and their molecular weights determined. These were compared to Literature values obtained by other laboratories. The agreement was quite good. Seven recombinant growth hormones were then investigated by this technique. The determined molecular weights were in agreement with the theoretical values. Differentiation between six of the seven analogs could be made on the basis of the molecular weight determinations. Two of these analogs differed in molecular weight by only 1 Da and the accuracy of the mass measurements was not sufficient for distinguishing these two homologous proteins. The influence of solvent on the mass accuracy determinations was studied. It appears that solvents form clusters with the proteins in the electrospray ionization method. These clusters broaden the peaks corresponding to the multiply charged ions of the proteins and make the determination of centroids more difficult.

The characteristics of visual scanning over the 2- to 14-week age period were examined through repeated assessments conducted on a sample of 10 infants. Scanning patterns were measured using a bright-pupil corneal reflex system, and the stimuli consisted of various sets of static, moving, or flickering geometric figures. There appear to be a number of age-related changes in the dominant mode of visual scanning. At the youngest ages the infants' scanning often proved unrelated to the locations of the stimulus contours, and in instances where a stimulus figure was in fact attended the infants typically centered their regard on a single prominent feature. In contrast, as the infants grew older they more consistently directed their saccades toward stimulus contours, became increasingly disposed to scan between different stimulus features, and directed their saccades with increased accuracy. When a stimulus was flickering, however, the infants' scanning characteristics reverted to those typically found at younger ages. The mechanisms which might account for the effects of age and of stimulus quality on visual scanning are considered.

The visual scanning characteristics of 10 infants were assessed repeatedly over the 2- to 14-week age period, using a bright-pupil/corneal reflection technique. The present report focuses on the calibration process--a procedure by which stimulus figures are mapped onto the raw scanning data. It is concluded that the major calibration parameters vary significantly among infants, and therefore separate calibration data must be collected on each infant if errors on the order of several degrees of visual angle are to be avoided. Moreover, it was found that infants' saccades often are not directed accurately toward the attracting stimulus, and hence repeated calibration trials are required for the precise determination of parameter values. After about 6 weeks of age, the parameter values established for a given infant remained largely invariant. During the initial weeks of life, however, parameter values occasionally changed, apparently because very young infants sometimes will center the image of an attracting stimulus about some extrafoveal location. This raises an additional complexity when interpreting the scanning records of very young infants.

The study seeks to illuminate the mechanisms that mediate avoidant reactions in young humans. 40 babies repeatedly were observed throughout their second year in a variety of mildly challenging situations, and then again in a series of follow-up assessments at age 3 1/2. Analysis of the covariance patterns among the repeated measurements supports positing 2 distinct types of avoidant mechanism--an inclination to be "wary" of the unfamilar, and a proclivity to be "fearful" after exposure to a mildly difficult situation. Each type of phenomena constituted an independent source of individual differences. Behaviors that differed as a result of prior experience proved fairly predictive of future social orientations; variations in initial wariness did not.

The profile of urinary metabolites of 3H-arbaprostil was characterized in the male dog after intravenous administration. The major metabolites were purified and their structures deduced by gas chromatography/mass spectrometry (GC/MS) studies after conversion to the methyl ester-methoxime-trimethylsilyl ether derivatives, aided by GC with simultaneous radioactivity monitoring. The identified metabolites accounted for 96% of the urinary excretion products. beta-Oxidation of the carboxy side-chain of arbaprostil to 15-methyl-2,3,4,5-tetranor PGE1, via the 15-methyl-2,3-dinor PGE2 intermediate, appeared to be the most significant metabolic pathway. In contrast to the rat, the following were observed in the dog: glucuronic acid conjugation of the 15-methyl-2,3,4,5-tetranor PGE, and PGA metabolites; detection of the 15-methyl-2,3-dinor PGE2 intermediate; absence of 19-hydroxyl-15-methyl-2,3,4,5-tetranor PGA, and PGB metabolites; oxidation at C-20; and excretion of some parent drug.