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The under-performance of supply chains presents a significant hindrance to disease control in developing countries. Stock-outs of essential medicines lead to treatment interruption which can force changes in patient drug regimens, drive drug resistance and increase mortality. This study is one of few to quantitatively evaluate the effectiveness of supply chain policies in reducing shortages and costs. This study develops a systems dynamics simulation model of the downstream supply chain for amikacin, a second-line tuberculosis drug using 10 years of South African data. We evaluate current supply chain performance in terms of reliability, responsiveness and agility, following the widely-used Supply Chain Operation Reference framework. We simulate 141 scenarios that represent different combinations of supplier characteristics, inventory management strategies and demand forecasting methods to identify the Pareto optimal set of management policies that jointly minimize the number of shortages and total cost. Despite long supplier lead times and unpredictable demand, the amikacin supply chain is 98% reliable and agile enough to accommodate a 20% increase in demand without a shortage. However, this is accomplished by overstocking amikacin by 167%, which incurs high holding costs. The responsiveness of suppliers is low: only 57% of orders are delivered to the central provincial drug depot within one month. We identify three Pareto optimal safety stock management policies. Short supplier lead time can produce Pareto optimal outcomes even in the absence of other optimal policies. This study produces concrete, actionable guidelines to cost-effectively reduce stock-outs by implementing optimal supply chain policies. Preferentially selecting drug suppliers with short lead times accommodates unexpected changes in demand. Optimal supply chain management should be an essential component of national policy to reduce the mortality rate. La médiocre performance des chaînes d’approvisionnement constitue un important obstacle à la lutte contre la maladie dans les pays en développement. Les ruptures de stock des médicaments essentiels entraînent une interruption du traitement qui peut contraindre à une modification des régimes posologiques des patients, favoriser la résistance aux médicaments et accroître la mortalité. La présente étude est l’une des rares à évaluer quantitativement l’efficacité des stratégies de la chaîne d’approvisionnement dans le cadre de la réduction des pénuries et des coûts. En se fondant sur les données recueillies au cours de 10 années en Afrique du Sud, l’étude développe un modèle de simulation de la dynamique en aval de la chaîne d’approvisionnement de l’amikacine, un antituberculeux de deuxième intention. Nous évaluons les performances actuelles de la chaîne d’approvisionnement en termes de fiabilité, de réactivité et de rapidité, en suivant le cadre de référence largement utilisé dans la gestion de la chaîne d’approvisionnement. Nous simulons 141 scénarios qui représentent différentes combinaisons de caractéristiques des fournisseurs, de stratégies de gestion des stocks et de méthodes de prévision de la demande afin d’identifier l’ensemble de politiques optimales de gestion au sens de Pareto, politiques qui minimisent aussi bien le nombre de pénuries que le coût total. En dépit de longs délais de livraison des fournisseurs et une demande imprévisible, la chaîne d’approvisionnement de l’amikacine est fiable à 98% et suffisamment rapide pour répondre à une augmentation de 20% de la demande sans occasionner de pénurie. Cependant, on ne peut y parvenir qu’avec un surstockage de l’amikacine à hauteur de 167%, ce qui entraîne des surcoûts considérables. La réactivité des fournisseurs est faible: seulement 57% des commandes sont livrées au dépôt central de médicaments de la province dans un délai d’un mois. Nous identifions trois stratégies de gestion optimale des stocks de sécurité au sens de Pareto. La réduction du délai de livraison des fournisseurs peut produire des résultats optimaux au sens de Pareto, même en l’absence d’autres politiques optimales. La présente étude élabore des directives concrètes et réalisables visant à réduire efficacement les ruptures de stock en mettant en œuvre des politiques optimales dans la chaîne d’approvisionnement. Sélectionner en priorité des fournisseurs de médicaments dont les délais de livraison sont les plus courts permet de s’adapter à des modifications inattendues de la demande. La gestion optimale de la chaîne d’approvisionnement devrait être une composante essentielle de la stratégie nationale visant à réduire le taux de mortalité. 供应链不佳给发展中国家疾病控制带来了严重阻碍。基本药 物短缺会干扰治疗, 导致患者用药方案被迫改变, 增加耐药和 死亡率。鲜有研究定量评估供应链政策在减少短缺和降低成 本方面的有效性, 本研究是其中之一。本研究采用南非的10年 数据, 建立二线抗结核药阿米卡星下游供应链的系统动力学模 拟模型。我们依据广泛应用的供应链运作参考框架, 评估供应 链的可靠性、反应性和灵活性。模拟了141个情境, 体现不同 的供应方特点、库存管理策略和需求预测方法的组合, 确定可 以最大程度减少短缺和总成本的Pareto最优管理政策组合。 虽然供应方前置时间长, 需求难以预测, 阿米卡星的供应链还 是具有98%的可靠性, 其灵活性也足以应对20%的需求增长而 不出现短缺。但上述结构是通过积压库存达167%实现的, 这 也增加了存货成本。供应方的反应性较低：只有57%的订单 在一个月内运到省中心药品仓库。我们发现了三项Pareto最 优安全库存管理政策。在没有其他最优政策的情况下, 仅缩短 供应方前置时间也可以带来Pareto最优结果。本研究产生了 具体、可行的指南, 通过实行最优供应链政策来有成本效益地 减少药品短缺。优先选择前置时间短的药品供应方可以适应 需求的意外变化。最优供应链管理应作为国家降低死亡率政 策的关键组成部分。 El bajo rendimiento de las cadenas de suministro presenta un obstáculo significativo para el control de enfermedades en los países en desarrollo. El agotamiento de las medicinas esenciales conduce a la interrupción del tratamiento, lo que puede forzar cambios en los regímenes farmacológicos del paciente, impulsar la resistencia a los medicamentos y aumentar la mortalidad. Este estudio es uno de los pocos que evalúa cuantitativamente la efectividad de las políticas de la cadena de suministro en la reducción de escasez y costos. Este estudio desarrolla un modelo de simulación de la dinámica de los sistemas de la cadena de suministro para la amikacina, un fármaco de segunda línea contra la tuberculosis usando 10 años de datos sudafricanos. Evaluamos el desempeño actual de la cadena de suministro en términos de confiabilidad, capacidad de respuesta y agilidad, siguiendo el ampliamente usado marco de Referencia de Operación de la Cadena de Suministro. Simulamos 141 escenarios que representan diferentes combinaciones de características de proveedores, estrategias de manejo de inventario y métodos de pronóstico de demanda para identificar el conjunto óptimo de Pareto de políticas de manejo que minimizan conjuntamente el número de periodos de escasez y el costo total. A pesar de los largos plazos de entrega de los proveedores y la demanda impredecible, la cadena de suministro de amikacina es 98% confiable y lo suficientemente ágil como para acomodar un aumento de 20% en la demanda sin escasez. Sin embargo, esto se logra sobrestimando la amikacina en un 167%, lo que conlleva altos costos de almacenamiento. La capacidad de respuesta de los proveedores es baja: solo el 57% de los pedidos se entregan al depósito central de medicamentos de la provincia en un mes. Identificamos tres políticas de manejo de existencias de seguridad del óptimo de Pareto. El corto plazo de entrega del proveedor puede producir resultados óptimos de Pareto incluso en ausencia de otras políticas óptimas. Este estudio produce pautas concretas y procesables para reducir los desabastecimientos de manera costo-efectiva mediante la implementación de políticas óptimas para la cadena de suministro. La selección preferencial de los proveedores de medicamentos con tiempos de entrega cortos acomoda cambios inesperados en la demanda. La gestión óptima de la cadena de suministro debe ser un componente esencial de la política nacional para reducir la tasa de mortalidad.

This study investigates the effect of a participative management practice, ‘mini-business activities’ (MBAs), on three outcome variables: team effectiveness, team innovation, and job satisfaction. An empirical approach is employed, with survey data gathered from 340 individuals working in 50 teams in South African manufacturing organisations. The results indicate that MBAs have a significant and positive effect on team effectiveness and team innovation in a similar way to that of quality circles. However, MBAs are found to have no direct or indirect effect, through employee engagement, on job satisfaction. The findings contribute to a more nuanced understanding of the impact of participative management practices in different contexts, and indicate that future research considering the impact of high unemployment levels on the relationship between participative management practices and job satisfaction would be valuable.

The source of gold in the ca. 2.66 Ga Black Reef Formation (BRF) has been investigated and constrained through petrographic, mineralogical, geochemical, and high-resolution three-dimensional reflection seismic data combined with drill core and underground geological mapping. The BRF is a strong seismic marker and consists of carbonaceous shale, quartz arenite, and conglomerate. Gold grade in the BRF is primarily controlled by the nature of the host conglomerates. Most of the gold in the BRF conglomerate occurs in native form, and its morphology is highly heterogeneous. Gold was initially introduced through mechanical recycling of underlying Witwatersrand reefs, followed by short-range (millimeter- to centimeter-scale) postdepositional alteration/remobilization associated with the Bushveld Complex and the Vredefort meteorite impact. Although the BRF was subjected to high postdepositional fluid circulation facilitated by high fracture density, the volume of dissolved gold was probably too small to form a large gold deposit, except in areas around the Black Reef/Witwatersrand reefs subcrop positions. Findings from this study demonstrate the importance of both sedimentological controls and impact-related structures in the formation of paleoplacer gold deposits during Neoarchean times.

Pharmacovigilance (PV) is based on the medical assessment of adverse medical events or drug-related problems, collected within organised health programmes. The large number of different PV systems, the equally large number of stakeholders within such systems (pharmaceutical companies, government regulatory bodies, national and international clinical regulatory bodies, healthcare workers, etc.), and the significant number of dimensions along which the effectiveness and efficiency could be measured, adds to this complexity. Furthermore, the lack of a standardised reporting protocol across the various PV systems hinders efforts to manage PV coherently on a global scale. This paper proposes the value of a standardised global PV reporting system by evaluating the systemic effects of the lack of such a standardised system.

Since 2010, pharmaceutical organisations have begun to provide drug patents in sub-Saharan Africa through the UN Medicine Patent Pool. This initiative allows any pharmaceutical manufacturer to access these patents and manufacture the drugs, thereby aiming to decrease the associated lead times and costs. The participation of numerous manufacturers, some of whom may not have well-established quality control systems in the market, intensifies the need for effective drug quality monitoring. Research indicates that it is often the case that these 'niche drug provision systems' face many challenges with the quality of new-generation drugs and the implementation of effective pharmacovigilance (PV)1 systems for the reporting of adverse drug reactions. The lack of resource efficiency in adverse drug reaction reporting within the sub-Saharan context is also a growing concern.

This article builds on earlier research that made the case for developing a framework to ensure increased, sustained, creative activity in engineering organisations. A milestone in the development of such a framework is the identification of the elements of creativity that need to be considered. This research reviews the literature on the systems perspective on creativity to identify seven elements of creativity that have been proposed in the literature. A literature review on each of these seven elements is presented to (i) determine whether the element should be included in the framework; (ii) define the element for the purpose of the framework; and (iii) determine whether any author proposes an aspect of creativity that cannot be accommodated under one of the seven elements as they have been defined here.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis 1 – 5 . However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance 6 . In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral transmission—as well as of pre-exposure prophylaxis, leading to new infections 1 , 2 , 4 , 7 – 9 . Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence 10 . Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log 10 -transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

Metaproteomics has matured into a powerful tool to assess functional interactions in microbial communities. While many metaproteomic workflows are available, the impact of method choice on results remains unclear. Here, we carry out a community-driven, multi-laboratory comparison in metaproteomics: the critical assessment of metaproteome investigation study (CAMPI). Based on well-established workflows, we evaluate the effect of sample preparation, mass spectrometry, and bioinformatic analysis using two samples: a simplified, laboratory-assembled human intestinal model and a human fecal sample. We observe that variability at the peptide level is predominantly due to sample processing workflows, with a smaller contribution of bioinformatic pipelines. These peptide-level differences largely disappear at the protein group level. While differences are observed for predicted community composition, similar functional profiles are obtained across workflows. CAMPI demonstrates the robustness of present-day metaproteomics research, serves as a template for multi-laboratory studies in metaproteomics, and provides publicly available data sets for benchmarking future developments.

Climate change and disturbance can alter invasion success of clonal plants by differentially affecting the clonal traits influencing their establishment as young plants. Clonal traits related to the vegetative reproduction of native Pascopyrum smithii and non-native Bromus inermis grass seedlings were evaluated under altered precipitation frequencies and a single grazing event. Pascopyrum smithii maintained similar vegetative reproduction under three simulated precipitation frequencies whereas B. inermis vegetative reproduction declined as precipitation became more intermittent. Vegetative reproduction of the non-native B. inermis was greater than the native P. smithii under all simulated precipitation frequencies except the most intermittent scenario. A single grazing event did not affect either species’ response to intra-annual precipitation variability but did slightly reduce their clonal growth and increase their bud dormancy. In young plants, clonal traits of the invasive grass favored its superior expansion and population growth compared to the native grass except under the most severe climate change scenario. Grassland restoration using native P. smithii seeds would be successful in most years due to its resilient clonal growth in a changing climate. Clonal infrastructure development in young plants is critical to clonal plant establishment and persistence in a changing climate and under disturbed conditions.

The structure, function, and dynamics of Earth's terrestrial ecosystems are profoundly influenced by how often (frequency) and how long (duration) they are inundated with water. A diverse array of natural and human-engineered systems experience temporally variable inundation whereby they fluctuate between inundated and non-inundated states. Variable inundation spans extreme events to predictable sub-daily cycles. Variably inundated ecosystems (VIEs) include hillslopes, non-perennial streams, wetlands, floodplains, temporary ponds, tidal systems, storm-impacted coastal zones, and human-engineered systems. VIEs are diverse in terms of inundation regimes, water chemistry and flow velocity, soil and sediment properties, vegetation, and many other properties. The spatial and temporal scales of variable inundation are vast, ranging from sub-meter to whole landscapes and from sub-hourly to multi-decadal. The broad range of system types and scales makes it challenging to predict the hydrology, biogeochemistry, ecology, and physical evolution of VIEs. Despite all experiencing the loss and gain of an overlying water column, VIEs are rarely considered together in conceptual, theoretical, modeling, or measurement frameworks and approaches. Studying VIEs together has the potential to generate mechanistic understanding that is transferable across a much broader range of environmental conditions, relative to knowledge generated by studying any one VIE type. We postulate that enhanced transferability will be important for predicting changes in VIE function in response to global change. Here we aim to catalyze cross-VIE science that studies drivers and impacts of variable inundation across Earth's VIEs. To this end, we complement expert mini-reviews of eight major VIE systems with overviews of VIE-relevant methods and challenges associated with scale. We conclude with perspectives on how cross-VIE science can derive transferable understanding via unifying conceptual models in which the impacts of variable inundation are studied across multi-dimensional environmental space.