The flora and vegetation of oceanic islands have been deeply affected by human settlement and further landscape modifications during prehistoric and historical times. The study of these transformations is of interest not only for understanding how current island biotas and ecological communities have been shaped but also for informing biodiversity and ecosystem conservation. This paper compares two oceanic insular entities of disparate geographical, environmental, biological, historical and cultural characteristics—Rapa Nui (Pacific Ocean) and the Azores Islands (Atlantic Ocean)—in terms of human settlement and further landscape anthropization. The similarities and differences between these islands/archipelagos are discussed considering their permanent colonization, the possibility of earlier settlements, the removal of the original forests and the further landscape transformations leading to either full floristic/vegetational degradation (Rapa Nui) or major replacement (Azores). This comparison uses evidence from varied disciplines, notably paleoecology, archaeology, anthropology and history, to obtain a holistic view of the development of the respective socioecological systems from a human ecodynamic perspective. The most relevant issues still to be resolved are identified and some prospects for future research are suggested. The cases of Rapa Nui and Azores Islands may help set a conceptual basis for ocean-wide global comparisons among oceanic islands/archipelagos. Most of these extinctions occurred in the Americas (30%), Africa (20%) and the Pacific islands (30%), followed by Eurasia, Australia and the Indo-Malayan region (<10% each) [Human settlement and landscape anthropization of oceanic islands is a topical issue that is able to provide small-scale models for understanding the effects of anthropogenic pressure on ecological dynamics, thus informing biodiversity and ecosystem conservation ,2,3. Ant0% each) . These nNot only extinctions but also profound ecosystem and landscape disruptions have been caused by the prehistoric and historical discovery and colonization of oceanic islands. Terrestrial insular ecosystems have been particularly affected by vegetation disturbance and the introduction of plants and vertebrates from elsewhere ,11,12,13This review compares two cases that are now actively discussed in the scientific literature and represent contrasting scenarios from geographical, environmental, biological, historical and cultural perspectives. One case is the subtropical Rapa Nui island  lying in the southeastern Pacific , which wThe review begins with a brief account of the main current features of the target islands , followeThe highly isolated and heavily anthropized Rapa Nui island and Azores archipelago have the same geological origin but differ in many environmental and biological features. Both island complexes were originated from hotspot volcanism, the first in the Pleistocene (0.8 million years ago or Ma)  and the 2) subtropical southeastern Pacific island  (2) islet Mottu Motiro Hiva , situated 400 km E-NE is not considered—the nearest island is Pitcairn (Polynesia), which is located ~2100 km west. Geographically, Rapa Nui is part of eastern Polynesia, but politically it belongs to Chile. Approximately 45% of the Rapa Nui inhabitants consider themselves as Rapanui, that is, descendants of the Polynesian colonizers (the ancient Rapanui), whereas the others are of Chilean origin, although genetic mixing between these groups is common [Rapa Nui is a small (164 km Long W)  that hass common .The climate is subtropical, with small seasonal temperature variations due to the oceanic influence. The annual average temperature is 21 °C with a gentle seasonal range of 5–6 °C on average, between 18 °C in the Austral winter (July–September) and 23–24 °C in the Austral summer (January–March). The total annual rainfall ranges between 1100 and 1300 mm. The average seasonal variability ranges between minima of 70–80 mm/month (November–December) and maxima of 100–130 mm/month (April–June). Potential evapotranspiration is approximately 850–950 mm/year; therefore, the climatic hydrological balance (precipitation-evapotranspiration ratio) is above 1, which means that there is no water deficit during a typical year . PrecipiAccording to the most recent update , the ext2 and the nine major islands mentioned range from 17 km2 (Corvo) to 745 km2 (São Miguel). The maximum elevations are between 587 m (Santa Maria) and 2350 m (Pico). The Azores are part of the biogeographical region known as Macaronesia, together with the subtropical Madeira and Canary Islands, and the tropical Cape Verde Islands, all of which are closer to the African coasts. Politically, the Azores are an autonomous region of Portugal and the society is typically Portuguese.The North Atlantic temperate archipelago of the Azores Islands  is situated ~1400 km west of Portugal (Europe), with Madeira (~900 km SE) as the nearest island. The archipelago is composed of three groups of islands: the Western Group (Corvo and Flores), the Central Group  and the Eastern Group (Santa Marta and São Miguel) . The totThe Azorean climate is temperate oceanic and is characterized by mild temperatures with small annual variations, a strong seasonal precipitation regime and significant interannual variability. At lower elevations, the average annual temperatures range from 16.7 °C (Terceira) to 17.5 °C (Corvo and Santa Maria) and the total annual precipitation is between 775 mm (Santa Maria) and 1716 mm (Flores). However, at higher elevations, average annual temperatures may decrease to 10.8 °C (900 m) and 6.2 °C (2000 m), and total annual precipitation may be over 4000 mm . MaximumRegarding floristic composition, 1110 species of vascular plants have been reported outside cultivation, of which 811 (73%) are considered part of the true Azorean flora, which includes all permanent and self-sustaining populations, whereas the remaining 299 (27%) are considered non established . Among tIn this paper, a differentiation is made among terms and concepts such as discovery, settlement and contact, along with their different types, as shown in The first paleoecological  studies on Rapa Nui sediments reported major island deforestation from ~800 CE, which was linked to the arrival of Polynesian colonizers ,45. SeveVerbena litoralis (Verbenaceae), a plant of tropical American origin that is presently widespread all over the island, in Lake Raraku sediments. This anthropochorous (dispersed by humans) plant, locally known as “puringa” and characteristic of agricultural and ruderal disturbed sites, was previously considered to have been introduced on the island in post-Columbian times (1492 CE), but is actually present in the Raraku sediments, in a continuous and abundant fashion, from 450 BCE to the present [V. litoralis pollen coincided with the first fires and a forest decline coeval with a grassland expansion (Sisyringium (probably S. michrantum) between 410 CE and 630 CE in the sediments of the Aroi bog. This plant is also of American origin and is now naturalized elsewhere. Other potential indications of human disturbance are the forest declines documented by 50–100 CE in Lake Kao [The recent finding of paleoecological evidence compatible with human presence in sediments older than 800 CE has suggested that the first settlement could have occurred earlier. Especially significant is the finding of pollen from  present . The appxpansion , which wLake Kao  and by 1Lake Kao . HoweverIpomoea batatas; Convolvulaceae), locally called “kumara”, is known to have been a fundamental food for ancient Polynesian societies, especially for Rapa Nui, where it has been suggested that the flourishment of the ancient Rapanui society would have not been possible without this plant [The sweet potato , along with spores from coprophilous fungi (notably Sporormiella) growing in the dung of herbivores [In the Azores Islands, any eventual settlement before Portuguese colonization in the mid-15th century may be considered an early settlement. As stated above, there is no archaeological evidence of this fact but paleoecological records are, once more, the most informative in this sense. The first palynological records documented significant vegetation changes, notably deforestation, just after Portuguese settlement, in the Corvo, Flores  and Pico  islands ,22. But rbivores  , at least 6–7.5 centuries before the Portuguese, and suggested that the first settlers would have been the Norse, with the aid of anomalous northeasterly winds and warmer temperatures . These cSecale pollen is represented only in the 13th century in the form of scattered occurrences [Zea) and wheat (Triticum), were omitted [The Norse hypothesis has also been questioned by Rull , who empurrences , but it urrences   or the accumulation of minor to major forest declines (progressive deforestation), in which case, stepwise forest declines are called forest decline pulses or events. All the above forest clearing patterns may occur at local (single-site) or general (island-wide) ambits.Jubaea chilensis) , Triumfetta (Tiliaceae), Macaranga and Acalypha (Euphorbiaceae), Coprosma (Rubiaceae), along with several unidentified Astraceae, Myrtaceae and Moraceae/Urticaceae [2, or 100–120 palms per km2) would have covered 70–80% of the island [According to the available palynological studies—historical documents did not appear until European contact (1722 CE), when the island had already been deforested—the pristine Rapa Nui forests were largely dominated by an unknown, likely extinct, palm species that is only known by its fruits very similar to the Chilean wine palm (ilensis)  and has disperta ,75. Otheticaceae . These pe island ,77.The classical literature on Rapa Nui usually considers a single type of forest removal, island-wide deforestation. However, the most recent studies have demonstrated that this process was heterogeneous in both space and time and that island-wide deforestation was actually the result of the accumulation of local minor to major forest declines and deforestation events . As mentThe first and last forest clearing events were recorded at Kao . The fir2 of mulching area, approximately half of the island surface, during a period between about 1460 and 1860 CE [Dioscorea alata; Dioscoreaceae), “ipu kaha” or bottle gourd , “taro” , “ti” , “mahute” or paper mulberry  and “maika” or banana , as documented by historical reports and pollen, phytoliths and starch grains from dryland soils and lake/swamp sediments [Regarding cultivation, the first records correspond to the already mentioned micro- and macrofossil remains of sweet potato, dated to 1300–1400 CE ,57. Smal 1860 CE . The proediments ,88,89,90Cocos nucifera), a second and even more intense landscape degradation phase took place as a result of the reactivation of extensive livestock practices. In 1903 CE, the island experienced the worst vegetation deterioration of its entire history. The introduction of exotic species continued with the planting of Eucalyptus forest stands, which are still standing on the island , Juniperus brevifolia (Cupressaceae), Prunus azorica (Rosaceae) and Morelle faya (Myricaceae), with other trees and shrubs, such as Frangula azorica (Rhamnaceae), Taxus baccata (Taxaceae), Picconia azorica (Oleaceae), Myrsine africana (Myrsinaceae), Viburnum tinus (Adoxaceae), and the Ericaceae Erica azorica, Vaccinium cylindraceum and Calluna vulgaris [The historical accounts of Portuguese settlers and the available palynological records coincide in that the pre-settlement forests were of the laurisilva type, that is, temperate evergreen forests with a predominance of species with laurus-like coriaceous shiny leaves that favor mist condensation on their surface thus creating a humid microhabitat . These lvulgaris ,91. Todavulgaris ,93. The vulgaris ,91.Juniperus, Ilex and Morella [Laurus pollen is poorly represented, but the local presence of this tree is documented by the occurrence of its characteristic stomata. Historical records document the overexploitation until exhaustion of many autochthonous plant species and communities—especially those useful for medical purposes, wood/charcoal extraction, fruit harvesting and the production of oils, dyes or materials for leather tanning, in which most of the abovementioned elements of native forests were involved—due to the colonialist mindset of the first settlers [During the pre-settlement phase, between Portuguese landing 1432 CE) and the official settlement (1449 CE), several types of domestic animals  were released on the uninhabited islands in the hope that their populations increased naturally and facilitated the establishment of eventual future colonizers in the absence of wild herbivores. It has been documented that these introductions were highly successful but the impact on primeval forests was minimal and of local nature. The proliferation of the introduced livestock suggests that natural open vegetation types other than laurisilvas were available for these animals to graze. These open communities would have been upland grasslands  and are 32 CE and Morella . In thessettlers .Saccharum officinarum), grape , pepper , pineapple  and especially orange . A detailed account of the transformative phase on São Miguel Island is provided by Moreira [The unsustainable exploitation of natural resources and their ensuing exhaustion led to the introduction of new production systems imported from the continent, such as wheat, sweet potato or corn cultivation, along with the expansion of upland pastures for animal husbandry. This inaugurated the transformative phase, which was especially active during the last two centuries. Other important monocultures developed during this phase were sugar cane ( Moreira  that couPittosporum undulatum (Pittosporaceae) was introduced as a hedgerow species to protect orange crops from wind. The orange industry declined by 1830 CE for economic reasons and because of the action of fungal and insect parasites. By 1860 CE, large-scale pineapple cultivation was introduced to replace orange crops. Again, large amounts of timber were needed for pineapple exportation, but the island was largely deforested and had to be reforested using several Pinus (Pinaceae) species imported from Europe, Cryptomeria japonica (Cupressaceae) from Japan, and Eucalyptus spp. (Myrtaceae) and Acacia melanoxylon (Fabaceae) from Australia. The decline of the remaining native forest elements such as Erica azorica and Myrsine africana, along with the introduction of Pinus pinaster and Cryotomeria japonica by 1750–850 CE, are manifest in the lake Azul pollen record. These introduced tree species, together with P. undulatum, still dominate the forests of São Miguel , which is native to the Himalayas and is dominant in the understory of many planted forests, mainly those of Cryptomeria. Another naturalized species that is widespread across the island, especially in ruderal habitats, is Hydrangea macrophylla (Hydrangeaceae), which is native to China and Japan (P. undulatum and Clethra arborea (introduced from Madeira) are the most successful invaders. Human pressure has been variable on the different islands, with Corvo and Flores being the least affected and São Miguel being among the most disturbed ones [During the 18th and 19th centuries, many exotic ornamental species were also introduced to decorate public and private parks and gardens. Some of these species have become naturalized and are successful invaders, such as nd Japan . Among tbed ones . São Migbed ones . The hisbed ones , and itsbed ones .In summary, the Azores Islands have not been fully deforested, and the extant forest formations are a mixture of native laurisilvas and newly assembled forest associations composed of alien tree species imported from elsewhere , not occurring naturally in their places of origin. The main deforestation events documented palynologically occurred by 1290 CE (São Miguel) and shortly after Portuguese settlement  and involved the main native laurisilva elements ,21. In tThe idea that environmental changes heavily influence human societies until the point that they may trigger cultural demises is known as environmental determinism and is opposed by those who consider that cultural developments are a consequence of exclusively human actions (human determinism). The debate is maintained by the difficulty of demonstrating that a given cultural change is actually a consequence of a particular environmental shift. In most cases, these inferences are based on chronological coincidences, but unequivocal mechanistic demonstrations remain elusive . This isThe Polynesians arrived in Rapa Nui some time during the Medieval Climate Anomaly , when warm/dry climates, higher sea levels and changes in wind patterns would have favored long-distance voyaging across the Pacific . AccordiOther paleoclimatic/paleoceanographic models suggest that, in addition to winds and currents, climatic variability would have been a major driver in Pacific colonization ventures and propose precipitation as a key parameter in this regard . The maiIn the classical literature, environmental shifts as drivers of ecological and cultural change on Rapa Nui have been systematically ignored by most archaeologists and explicitly dismissed by some paleoecologists. For example, Bahn & Flenley  argued tThis type of feedbacks and synergies between climate and humans had not been previously considered in the Rapa Nui literature and opened a new opportunity for a holistic approach in the analysis of socioecological systems, known as EHLFS (environment-human-landscape feedbacks and synergies) . The EHLIn their proposal for an early settlement by Norse people and the associated widespread landscape anthropization, Raposeiro et al.  utilizedThe first paleoecological reconstructions from the Pico and Flores islands  emphasizAlthough Rapa Nui is more distant than the Azores from both the mainland and the nearest island, the species/area relationship, a key parameter in island biogeography since the time of McArthur & Wilson , is >3.5Floristically, the degree of anthropization is very similar with approximately three quarters species introduced and the others are native, in both cases . The maiVerbena and Sisyringium, suggesting potential pre-Polynesian connections with South America, a possibility that has been supported by recent genetic analyses of other American domesticates, notably the sweet potato, and human populations. Interestingly, the most consistent and widespread paleoecological evidence for early Azorean colonizers corresponds to dates (1200–1400 CE) similar to the Polyensian settlement of Rapa Nui. This indicates that, despite the disparate geographical position in two different oceans, the different origin and cultural features of the colonizers and the different navigation technology and trajectories needed to arrive at Rapa Nui and the Azores, they were probably settled during the same time window, in the transition between the MCA and the LIA  and Portuguese (Azores) colonization. In both cases, early settlers would have consisted of local ephemeral and/or intermittent populations practicing small-scale cultivation and animal husbandry, who did not leave archaeological remains or their traces were too faint that they were erased with time or by further permanent settlers. In Rapa Nui, early settlers would have introduced tropical American anthropochorous weeds, such as  the LIA . The difThe combination of archaeological and paleoecological evidence, together with paleoclimatic/paleoceanographic reconstructions agree that Polynesian settlement would have occurred approximately 1200 CE (1150–1300 CE), approximately two centuries and a half prior the Portuguese occupation of the Azores. Polynesians arrived in Easter Island after a millennial transpacific journey starting 5000 years ago (3000 BCE), when Taiwanese sailors colonized the Philippines . The nexThe navigation skills of ancient Pacific peoples are well known, and developments such as the double-hulled canoe or the star-and-wind compass are outstanding examples . With thA fundamental difference between Rapa Nui and the Azores is that the former was fully deforested by 1600 CE, whereas in the latter, the progressive decline of native forests due to their overexploitation, was compensated by a widespread reforestation (18th century onward) with alien species from diverse origins. These introduced forests have acclimated very well to the archipelago and are so dense, healthy and exuberant that they could seem pristine to an unaware visitor. Another difference is that, in Rapa Nui, forest clearing pulses did not coincide chronologically on the studied localities, whereas in the Azores, two clusters of clearing events were documented by 1200–1450 CE (before and at the beginning of Portuguese occupation) and by 1700 CE , involving islands from the three geographical groups . The firThe progressive replacement of Rapa Nui palm forests by gardened lands coincided chronologically with the extractive phase in the Azores . TherefoThere is sound evidence for early ephemera/intermittent settlement in both Rapa Nui and the Azores, prior to Polynesian and Portuguese permanent settlement, respectively. In Rapa Nui, this evidence dates to a couple of millennia ago and points toward a potential Amerindian origin, as proposed by the long discredited Heyerdahl’s hypothesis. In the Azores, the evidence is much more recent (13th–14th centuries) and there is no indication of the origin of the early settlers.According to archaeological evidence, the permanent Polynesian settlement of Rapa Nui (1200–1300 CE) would have occurred a couple of centuries prior to that of the Azores by Portuguese (1449 CE), which is well documented historically. The permanent settlement of Rapa Nui was the culmination of a millennial-scale process of occupation of virtually all Pacific islands/archipelagos from eastern Asia, whereas the occupation of the Azores occurred at the beginning of the expansion of the Portuguese empire. In this expansion, the Portuguese arrived in Papua New Guinea approximately 3000 years after the ancient Asian colonizers.Rapa Nui was fully deforested by 1600 CE, whereas the primeval Azores forests were never totally removed and occupy a small percentage (<3%) of the total surface. The remaining total forest cover was planted during the last two centuries using allochthonous tree species from Europe, Japan and Australia, which have been successfully naturalized. The Rapa Nui deforestation was the sum of local and apparently random forest clearing pulses, whereas in the Azores, forest clearing events were of the same type at the beginning and became more widespread after permanent settlement.Major landscape transformations occurred at similar times (15th–18th centuries) in both Rapa Nui and the Azores, and the same was true for the time of maximum landscape anthropization (19th century), which was characterized by full land degradation in Rapa Nui and widespread vegetation replacement in the Azores.Presently, although Rapa Nui is much smaller and more isolated than the Azores, the species/area relationship is almost four times larger in the first. The percentage of endemic species is more than two times greater in the Azores. The anthropization index is almost the same if we consider the flora (three quarters of which is introduced in both cases), but is lower in the Azores if the vegetation is taken into account. Indeed, no traces of native vegetation remain on Rapa Nui, whereas in the Azores, it occupies approximately 13% of the total surface.A summary of the similarities and differences is provided in Much work is still to be done for a thorough assessment on human settlement and landscape transformation in Rapa Nui and the Azores. Early settlement is a key point and, although it is consistently supported by the available evidence, its spatiotemporal patterns remain largely unknown and need further paleoecological, archaeological and anthropological research for a sound assessment. In Rapa Nui, the use of molecular biomarkers for human presence and activities is still lacking and could be instrumental in clarifying the origin and cultural features of potential early settlers. In the Azores, more records encompassing the last millennia across the whole archipelago are still needed for an archipelago-wide appraisal. Another important aspect that remains hypothetical is the influence of environmental (mainly climatic) changes on the studied island socioecosystems. The available paleoclimatic and paleoecological records are supportive of meaningful environment-human-landscape feedbacks and synergies, but the finding of new records and the use of novel proxies are needed for an unequivocal assessment and the establishment of causal relationships. Paleoclimatic trends of the last millennia remain largely unknown or are rather contradictory in both Rapa Nui and the Azores, and further research is needed to clarify this point. The development of new lake/swamp coring campaigns is encouraged to establish a coherent paleoenvironmental framework to be compared with the available archaeological, anthropological and historical information in the way toward a holistic view using human ecodynamic approaches such as the EHLFS or similar approaches . This in


This study aims to characterize the June 2020 COVID-19 outbreak at San Quentin California State Prison and to describe what made San Quentin so vulnerable to uncontrolled transmission.Since its onset, the COVID-19 pandemic has exposed and exacerbated the profound health harms of carceral settings, such that nearly half of state prisons reported COVID-19 infection rates that were four or more times (and up to 15 times) the rate found in the state’s general population. Thus, addressing the public health crises and inequities of carceral settings during a respiratory pandemic requires analyzing the myriad factors shaping them. In this study, we reported observations and findings from environmental risk assessments during visits to San Quentin California State Prison. We complemented our assessments with analyses of administrative data.For future respiratory pathogens that cannot be prevented with effective vaccines, this study argues that outbreaks will no doubt occur again without robust implementation of additional levels of preparedness – improved ventilation, air filtration, decarceration with emergency evacuation planning – alongside addressing the vulnerabilities of carceral settings themselves.This study addresses two critical aspects that are insufficiently covered in the literature: how to prepare processes to safely implement emergency epidemic measures when needed, such as potential evacuation, and how to address unique challenges throughout an evolving pandemic for each carceral setting. The coronavirus disease 2019 (COVID-19) pandemic has exposed the profound public health dangers posed by carceral settings, which imprison some of society’s most medically marginalized people . As we pThe scientific literature has documented what makes carceral settings dangerous, characterized outbreaks associated with the severe acute respiratory syndrome coronavirus 2  in carceral settings and identified priorities to address COVID-19 in these settings, notably population reduction, ventilation, appropriate mask use, quarantine, medical isolation and high vaccination rates once effective vaccines became available . This arOn June 13, 2020, two weeks after 122 incarcerated people were transferred (with an undetermined number having COVID-19) to San Quentin, members of our multidisciplinary team of clinicians, epidemiologists, exposure scientists and health policy researchers visited the prison to evaluate the risk of an uncontrolled outbreak. We went at the request of the Federal Receivership which oversees healthcare in California state prisons. Over the course of the pandemic, the California Department of Corrections and Rehabilitation (CDCR), with the second largest state prison population in the USA, has experienced a devastating series of COVID-19 outbreaks throughout its 35 prisons, without a single facility spared. The San Quentin outbreak was an extreme example of an explosive outbreak that spread to 2,241 (62.3%) incarcerated people and 445 (27%) staff during the outbreak.On the morning of our visit, the institution had approximately 20 confirmed active cases. Two days later, we issued an urgent memo  describiSome data presented in this paper include summaries of de-identified administrative and health records ranging from January 1, 2019, to July 17, 2021, which were provided to the authors by the CDCR and California Correctional Health Care Services (CCHCS). The University of California (UC), San Francisco Human Research Protection Program Institutional Review Board (IRB) (IRB#: 21–34030) has approved the use of this data for research under 45 CFR 305(a), and the data use protocol is also registered in the UC Berkeley IRB Reliance Registry (Study #3755).Other data presented in this paper are derived from observations during an on-site assessment conducted on June 13, 2020, at San Quentin State Prison in California, as well as subsequent visits to the institution in 2021. The assessment and subsequent visits were requested by the office of the California Prison Health Care Receivership to assess the risks within the environment for SARS-CoV-2 transmission. Our on-site assessment and use of publicly available data did not involve experimental protocols. Using their self-assessment tool, the UC Berkeley Committee for the Protections of Human Subjects determined that under Federal Regulations 21 CFR 50.3 and 45 CFR 46.102, our quality improvement activities were not deemed “human subjects research” and written, informed consent was not required for this assessment. All methods were carried out in accordance with relevant guidelines and regulations.In early 2020, the California Institute for Men (CIM), another CDCR prison, was experiencing a rapidly evolving, facility-wide COVID-19 outbreak. With increasingly limited options to minimize transmission risk, CIM leaders assessed and identified people at increased risk for adverse COVID-19 outcomes (primarily from dormitories) for transfer to cells at San Quentin. At the time, San Quentin’s population was at 114% of architectural design capacity, a decrease from 135% in January 2020.On May 30, 2020, 122 incarcerated people from CIM boarded five buses to San Quentin, which had yet to have any known COVID-19 infections . Upon arOnce SARS-CoV-2 entered San Quentin, few preventive actions recommended for containing community spread could be implemented to slow the rapid pace of transmission. This problem was not new but was described a century ago when San Quentin experienced three 1918 influenza outbreaks . Despite the fact that using cells normally used for punishment for quarantine has been associated with documented health harms  have solid floors, solid ceilings and solid walls on three sides. Nearly, all the cells have bars or perforated metal on the fourth side, which faces an open atrium spanning all floors. Because air circulates freely out of one cell and into another, each cellblock functions more like a dormitory rather than a facility with isolated prison cells.Further, San Quentin’s cellblocks were originally built with large windows to provide cross-ventilation, but in recent years those have been welded shut, preventing natural ventilation for the buildings as originally designed. Fresh air is introduced to the cellblocks via a mechanical system that brings fresh air onto the first floor. A circulating fan on the fifth floor circulates air within each building. The circulation and mixing of air ensure that fresh air and, in the wintertime, heated air are distributed to each floor in the five-floor cellblock. This mixing mechanism may also serve to transport infectious viruses from one area to another, especially because there is no solid door separating infected individuals from uninfected individuals and common areas.While circulated air is passed through a filter on circulation fans, filters were low-grade pleated filters not rated for viral particle removal . Given tManaging the outbreak required additional human resources to provide urgent medical care to the large numbers of people who were sick and testing positive for SARS-CoV-2, make quarantine and medical isolation decisions, liaise with community hospitals, address environmental risk factors  and ensure the safe movement and security of incarcerated people and staff. Absence of previously developed epidemic response plans  further stressed staff capacity as staff were required to develop plans during the emergency, while putting aside their existing responsibilities.Timely test results facilitate decisions about control measures like medical isolation and quarantine to prevent onward spread of SARS-CoV-2. It is important to underscore the relationship between the built environment and testing delays. While we do not believe that it is possible to avoid large outbreaks in settings like San Quentin based on current design, we also do not know how much the attack rate could have been reduced had rapid-turnaround testing been available and had the environmental controls identified been immediately implemented. When COVID-19 was introduced into a San Quentin cellblock, there was no more urgent need for rapid-turnaround testing in the state , such a lack of staff separation in units with active infections likely interfered with the goal of containing an outbreak to a single housing unit.Together, these vulnerabilities created an environment which required extreme and additional levels of mitigation. Superspreader events have tended to involve crowds, singing or shouting, poorly ventilated spaces and a lack of adequate face coverings , this manuscript is focused on outbreak control lessons for when vaccines are unavailable or not highly protective.Given that SARS-CoV-2 is highly contagious through aerosols, which was not recognized by many national public health authorities at the time of the outbreak, a similar situation at San Quentin in the future would warrant an unprecedented emergency evacuation in a matter of days to prevent the rapid transmission observed over 2–3 weeks. In this section, we deconstruct in greater detail two key measures that were not adequately anticipated at San Quentin.As SARS-CoV-2 is transmitted from infectious individuals through droplets and aerosols, appropriate building ventilation and filtration systems are important in controlling indoor aerosol transmission risks . It has The lack of sufficient appreciation of the role of aerosols in SARS-CoV-2 transmission also reduced the perceived urgency of implementing well-known controls for preventing rapid spread of a respiratory pathogen in an indoor congregate space . Emergency decarceration is a costly and potentially dangerous activity; however, if an evaluation of whether someone can be safely decarcerated is only done after an outbreak has occurred, then it will likely take too long to make that assessment and achieve decarceration quickly enough.In any high-risk setting, there must be prior assessments (e.g. as soon as a pandemic is declared) of who could be decarcerated into: the community (e.g. to family), an unsecure community setting (e.g. an unsecured hotel), a low-security alternative facility  and who would either need to remain in the facility or be transferred to another correctional facility. The plan must include a process for rapidly making the decision to decarcerate (delayed decarceration is ineffective with a rapidly spreading pathogen).Further, that process must include an assessment of the risk associated with an introduction of a pathogen into that specific facility and the harm associated with the specific pathogen for both incarcerated people and staff. Prior discussion must include what level of expected morbidity and mortality would be high enough to trigger emergency decarceration. For example, if decision-makers had assessed that the expected community-level mortality for a population of the size and age of San Quentin would have been eight individuals and that the projected mortality in San Quentin without decarceration was 28 , would averting those 20 additional deaths from COVID outweigh the cost and potential dangers of emergency decarceration?When an outbreak occurs, leadership must take immediate steps to stop transmission in affected housing units, minimize the probability of spread to other housing units and further reduce the risk of rapid spread among groups by reducing maximum occupancy of congregate spaces. This requires planning and implementing three levels of safety: not exceeding safe occupancy under non-epidemic circumstances; emergency reduction of occupancy of high-risk housing units when faced with an epidemic to further reduce transmission risks within the facility; and further emergency reduction of occupancy when an outbreak occurs within an institution (converting affected housing units into safe quarantine and reducing risk in unaffected housing units). This must depend upon a specific pathogen’s transmissibility and lethality.In March 2020, CDCR prisons averaged 130% design capacity (range: 91%–170%). While addressing overcrowding by decarceration during the COVID-19 pandemic is a recommendation based on public health guidance, implementing this recommendation has been difficult and politically fraught. Between April 2020 and July 2021, CDCR accelerated the release of incarcerated persons, primarily people close to the end of their sentences and a small number of medically vulnerable individuals. These efforts have been documented both before and during the COVID-19 pandemic. The primary driver in occupancy reduction was suspension of intake from local jails.Decarceration, a combination of early release with reentry support, furlough (temporary release) and alternative  confinement, can be considered in an intersectional community effort that is not only effective as a public health intervention, but an integral component of both public safety and community rebuilding. Emergency decarceration measures – alongside reentry planning–should be part of any future prison pandemic preparedness plan.Approaches to emergency evacuation of high-risk housing units have been reviewed elsewhere . Inside At this time in the COVID-19 pandemic, decarceration and high levels of vaccine coverage are especially important in large congregate units or areas with shared airspace where ventilation or air filtration cannot be fully achieved, as is the case in many carceral facilities. In the event of a future introduction of an infectious disease that has a higher mortality rate and a lack of effective vaccines, it is clear that prisons should have a plan in place that identifies threat level(s) for when emergency actions (such as decarceration) should be implemented and procedures that enable leadership to make that decision. The lessons from San Quentin prison are instructive for all settings that are infrastructurally incapable of keeping thousands of people safe during a respiratory outbreak. The lessons also speak to the urgency of better preparing for our next uncontrollable outbreak. With over 10 million people incarcerated around the world, 2.1 million of whom live in 5,000 carceral facilities in the USA, further research is urgently needed to inform the most appropriate and the safest levels of multi-layered mitigation strategies, including ventilation and decarceration measures, to protect against respiratory pathogens in these settings.The authors would like to thank the individuals at the Office of the California Prison Health Care Receivership and the health care and correctional leadership, staff, plant and engineering staff and those who are incarcerated at San Quentin. The authors thank Elizabeth Noth for her conversations and support and Catherine Duarte for her inputs and review of earlier drafts. The authors are grateful for CDCR and CCHCS’ transparency and willingness to collaborate. The authors offer their deep appreciation and gratitude to all frontline staff, leadership, incarcerated persons, families and advocates working to respond to COVID-19 in the US prisons.Funding: The results of this manuscript are based on an evaluation of a COVID-outbreak at a prison in California funded by the Office of the California Prison Health Care Receivership, which oversees delivery of health-care services in California’s state prison system. BW’s efforts on this manuscript were supported by the National Institute on Aging, National Institutes of Health under the Aging Research in Criminal Justice Health Network (grant R24AG065175). The authors retained full independence in writing the manuscript, including data collection, analyses and interpretation of results.Competing interests: BW has served as an expert witness and as a court consultant in legal cases related to prison conditions of confinement. These relationships have included the National American Civil Liberties Union and the Center for Constitutional Rights. BW and SB volunteer on an Advisory Board to Federal Judge Tigar who oversees the Plata correctional healthcare lawsuit in California prisons. None of these entities supported or influenced the submitted work.


A comprehensive understanding of subgroups of community-dwelling older adults and their long-term care (LTC) utilization can help to promote equality in the long-term services and support system. Dependency and household characteristics were found to affect the LTC utilization of homebound older adults. However, few studies considered the typologies of dependency of older populations according to co-occurring limitations, and little is known about differences in LTC use among elderly of typologies of dependency under distinct household conditions.We aimed to identify typologies of dependency of older adults living at home and explore the disparities in formal care and informal care use among typologies of dependency by income and living situation. In this cross-sectional study, we used the public long-term care insurance (LTCI) database of Yiwu, Zhejiang Province, China, and included 1675 individuals aged ≥ 60 years living at home. Cluster analysis was conducted to determine typologies of dependency among older adults. A two-step multilevel analysis was used to examine disparities in formal and informal care use related to household income and living status among typologies of dependency.Seven dependency clusters were identified. Pro-wealthy inequalities in both formal and informal care use were found in the least dependent cluster and the limited-locomotion cluster. Pro-poor inequalities in formal care use were found in the fully dependent cluster without impaired vision and the cluster with intact continence and vision. Living with family members was positively associated with receiving formal care for the fully dependent cluster. Older adults in most clusters were more likely to use informal care when living with family members, except for the least dependent cluster and the limited-locomotion cluster.Our findings suggest that household inequalities in LTC use varied among typologies of dependency of older adults, which may provide insights for researchers and policymakers to develop tailored LTC and targeted LTCI programs for older adults living at home and their family caregivers, considering both typologies of dependency and household characteristics. Population aging is one of the current challenges in most countries, putting enormous pressure on health and social security systems . Such deDependency is a key individual determinant for long-term care (LTC) use . DependePerson-oriented analyses, such as cluster analysis or latent class analysis (LCA), which use patterns of scores across cases to identify individuals who can be grouped together , provideNotably, understanding the characteristics of long-term care (LTC) use is critical to estimating society’s demand for and costs of services . The varFrom a policy perspective, care time is often used to estimate care costs and the burden on family caregivers, as well as to justify access to nursing homes, support staff, and financing by older people with disability, as it represents the service intensity related to the difficulty with providing assistance for elderly disabled adults and implies individual functional traits to a larger extent –29. HoweThus, in this study, we aimed: (1) to identify typologies of dependency among older adults with physical disabilities who require LTC, using public LTCI claimant data of 1675 older people in the city of Yiwu, Zhejiang Province, China; and (2) to examine disparities in formal and informal care use times on cluster level (subgroups of typologies of dependency), by income and living situation. The results of this study will offer a nuanced understanding of household socioeconomic inequality in LTC use among subgroups of typologies of dependency, and will be helpful for researchers and policymakers to improve care service provision and insurance payment policies for older adults through considering their functional limitation typologies as well as household conditions.For this cross-sectional study, we obtained data from the public LTCI database of Yiwu in Zhejiang Province, China. As the key contact city in China’s National Long-term Care Insurance Pilot Project, Yiwu had a total of 1.07 million insured permanent residents as of 2018, and 10% of them were aged ≥ 60 years. Yiwu LTCI was initiated in September 2018, and the target population was adults aged 60 years. A set of standardized assessments was administered by trained professionals who visited claimants’ homes or facilities to determine the qualifications for being an LTCI beneficiary. Eligible older adults were ≥ 60 years and received the qualification assessment between 1 September and 31 December 2018 . We inclIn this study formal care use time and informal care use time were two dependent variables, and were assessed using two self-reported items, respectively: “In the past 3 months, how many hours per month, on average, did you use paid long-term care?” “In the past 3 months, how many hours per month, on average, did you use unpaid long-term care?” Hours of use of both formal and informal care were log-transformed.We focused on two aspects of individual determinants: typologies of dependency and household characteristics. (1) Typologies of dependency. We chose 19 items to identify typologies of dependency among participants, involving an assessment of mobility, self-care, urinary and fecal continence, locomotion, vision, and money management based on prior literature  and the Age, sex, marital status, and educational attainment were considered confounders and were self-reported, as follows: (1) age (years); (2) sex ; (3) marital status ; and (4) educational attainment . In this study, self-rated health (SRH) was measured by the following single question: “How do you feel about your overall health, looking at the recent seven days?” This single-item questionnaire is considered a validated measure to reflect SRH and has been widely used in previous studies .PossibleCluster analysis was used to identify typologies of dependency among elderly participants (for aim 1). K-means clustering was performed and the optimal number of clusters was determined based on the elbow method , as wellTwostep is a bundle of programs to ease multilevel analyses with the “twostep approach”, and is easily applied in Stata by command twostep [For aim 2, first, one-way analysis of variance and cross tabulation were used to investigate between-cluster differences in sociodemographic variables, self-care health score, formal and informal use time, and additionally, by different income groups and living status groups. Then, we used two-step multilevel analysis to examine disparities in formal and informal care use times on cluster level (subgroups of typologies of dependency), by income and living situation, adjusting for confounders as mentioned above.  twostep . We usedTable Figure Table Figure Figure In this study, we identified seven functionally limited clusters among Chinese elderly claimants of public LTCI and examined the relationship between typologies of dependency and formal and informal care use by income and living situation. An important contribution of this study is the introduction of qualitative measurement of dependency, which expands the understanding of LTC use in older adults from the perspective of dependency cluster grouping. To our knowledge, this was the first study to examine and compare LTC use among typologies of dependency in the context of the Chinese LTCI.Using cluster analysis, seven typologies of dependency were identified in the population: fully dependent without impaired vision, fully dependent, intact vision and transfer, intact continence and vision, able to groom, limited locomotion, and least dependent. Previous research using the same techniques has identified five functional limitation patterns among the community-dwelling US population using data from the Health and Retirement study: no difficulty, difficulty pushing/pulling, difficulty lifting, difficulty climbing stairs, and difficulty with the upper body . Such diOf the seven clusters, the fully dependent cluster had the most formal and informal care time per month; the least dependent cluster had the least formal and informal care time per month. These findings are consistent with previous studies, which showed that, on the whole, older people with severer dependency used more LTC . NotablyIn this study, we also descriptively compared the LTC use among typologies of dependency with different household characteristics. We observed a great disparity in care time for both formal and informal care between clusters in the low-income group; in the high-income group, these differences were very small. This implied that older adults with low household income may be more affected by their typologies of dependency. Household income was positively associated with greater health awareness , lower hWhen examining the inequality in terms of household income with respect to LTC use of clusters, we found a pro-poor inequality in formal care use in the fully dependent without impaired vision cluster and intact continence and vision cluster, contrasting with the findings of previous research . This maWith respect to informal care, inconsistent with prior studies , we founPrevious research has shown that living status has an impact on inequalities in LTC use for older adults, as it might determine access to informal care or the ability to count on potential “advocates” in receiving LTC services , 24, 25.Existing studies do not provide a consensus regarding the inequality by SES in LTC use due to the mixed effect among individual health status and household conditions , 18, 36.These findings may inform the design and implementation of future interventions. For example, VI screening and early identification of VI among older adults are needed , which cSome limitations of this study should be mentioned. First, this was a cross-sectional study, which precluded inference regarding causality. Second, the study sample comprised potentially physically disabled older people and was not population-based. Therefore, these findings may not be generalizable to the whole population of older adults. Third, the role of external factors in LTC service utilization was not examined in this study. Caution should be exercised in comparing and explaining the LTC use of elderly individuals. Further research is needed to clarify the complex mechanism of LTC use using detailed longitudinal data covering individual and external factors. Fourth, while our empirical data supported the seven subgroups of typologies of dependency, and this result is similar with other research carried out in China using an alternative method (e.g. LCA) ; the sevThis study contributed to a better understanding of typologies of dependency and inequalities in LTC use among potentially physically disabled older people living at home in China. Our findings suggest that socioeconomic inequality in terms of household characteristics varies among typologies of dependency. These results could provide insights for researchers and policymakers to develop tailored LTC and targeted LTCI programs for older adults living at home and their family caregivers considering typologies of dependency and household conditions as a whole.


Since 1980, the US Congress has passed legislation providing several incentives to encourage the development and regulatory approval of new drugs, particularly antibiotics. We assessed long-term trends and characteristics of approvals and discontinuations of all new molecular entities, new therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA), as well as reasons for discontinuations by therapeutic class, in the context of laws and regulations implemented over the past four decades. In the period 1980–2021, the FDA approved 1310 new drugs, of which 210 (16.0%) had been discontinued as of 31 December 2021, including 38 (2.9%) withdrawn for safety reasons. The FDA approved 77 (5.9%) new systemic antibiotics, of which 32 (41.6%) had been discontinued at the end of the observation period, including 6 (7.8%) safety withdrawals. Since the enactment of the FDA Safety and Innovation Act in 2012, which created the Qualified Infectious Disease Product designation for antiinfectives to treat serious or life-threatening diseases due to resistant or potentially resistant bacteria, the FDA has approved 15 new systemic antibiotics, all using non-inferiority trials, for 22 indications and five different infections. Only one of the infections had labeled indications for patients with drug-resistant pathogens. Over the past 40 years, the US Congress has enacted laws aimed at accelerating the development and speeding the regulatory review and approval of pharmaceuticals in general and new systemic antibiotics in particular. In 1992, the Prescription Drug User Fee Act (PDUFA) authorized the Food and Drug Administration (FDA) to collect fees from pharmaceutical companies to shorten the FDA’s regulatory review time for new drugs, including systemic antibiotics. In 1997, the FDA Modernization Act (FDAMA) extended drug market exclusivities and patent extensions to antibiotics to encourage the development of new systemic antibiotics. In 2012, the Generating Antibiotic Incentives Now (GAIN) Act was passed as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA (2012) amended the accelerated approval pathway and the fast track and breakthrough therapy designations for eligible new antibacterial and antifungal drugs intended to treat serious or life-threatening infections. FDASIA also created the qualifying infectious disease product (QIDP) designation for anti-infectives, speeding review times for drugs intended to treat serious or life-threatening infections caused by antibacterial or antifungal resistant pathogens. This law directed the FDA to create a list of qualifying pathogens that have the potential to pose a serious threat to public health and added five years of market exclusivity, in addition to any other exclusivity periods applicable under the Hatch–Waxman Act, for qualified infectious disease products without requiring evidence of improved patient outcomes [Drug sponsor companies may discontinue approved drugs from the market at any time without warning. The only exception to drug market discontinuations is in cases of a potential disruption in the US market supply, in which case companies must notify the FDA of drug discontinuations at least six months in advance. Likewise, the FDA may withdraw approval of a drug application or an approved drug at any given time due to safety or efficacy-related reasons . AccordiPrior studies evaluating the approval and discontinuation of antibiotic drugs were constrained by limited timeframes and did not assess the impact of major regulatory actions passed in the United States ,6,7. MorThis observational study included all new molecular entities (NME—a new drug containing an active ingredient that has never been approved before for marketing in the US), new therapeutic biologics regulated by the FDA Centers for Drug Evaluation and Research (CDER), and gene and cell therapies regulated by the Centers for Biologic Evaluation and Research (CBER), approved by the FDA in the period 1980–2021.We extracted data for each FDA-approved NME, biologic license application, and gene and cell therapy, including the new drug application number, filling and approval dates, product number and type of application, active ingredient, generic and brand names, dosage form and administration route, National Drug Code, and market status. We also collected information on the FDA approval pathway  and orphan drug designation. NMEs and therapeutic biologics data were derived from the Orange Book, Drugs@FDA, and Purple Book, respectively. Gene and cell therapy data were derived from the list of approved cellular and gene therapy products approved in the US available at the CBER ,9,10,11.We collected study data according to a predetermined protocol using a standardized data extraction form developed and piloted by the authors and used in prior studies . To ensuA drug was defined as discontinued from the US market as of 31 December 2021, if the FDA had released a notice of discontinuation of approval in the Federal Register, the drug was listed as discontinued in the market status section of the Drug@FDA database, the drug was no longer included in the Orange Book (OB) listing of approved applications, or it was listed in the OB discontinuation section. Drug withdrawal data for safety reasons were derived from the Federal Register, the FDA Safety Information and Adverse Event Reporting Program (MedWatch), and other safety communications available at the FDA webpage ,15,16.The unit of analysis was the first new drug application or biologic license application for each NME, new therapeutic biologic, and gene and cell therapy approved by the FDA during the study period. We assessed trends over time in approvals and discontinuations of systemic antibiotics and all other new drugs approved by the FDA during the period by four distinct regulatory periods  demarcated by the enactment of major regulatory actions.We conducted descriptive analyses for study variables including approvals, discontinuations, and safety withdrawals. We used the non-parametric Pearson’s chi-squared test of independence to assess differences in market discontinuations and safety withdrawals among therapeutic categories. The significance level was set at 0.05. All analyses were performed using R.In the period 1980–2021, the FDA approved 1310 new drugs. The therapeutic class with the greatest number of approvals was antineoplastic drugs , followed by the central nervous system , and the alimentary tract and metabolism . Approvals of antineoplastic and immunomodulating agents increased steadily over time from an annual average of 2.0 drugs  prior to PDUFA to 19.5  after the enactment of the 21st Century Cures Act . Conversp < 0.05) except for diagnostic drugs (p = 0.690) and antiparasitic products, insecticides, and repellents (p = 0.273) (p = 0.004), the nervous system (p = 0.025), diagnostic drugs (p = 0.037), and antivirals for systemic use (p = 0.021). All discontinued systemic antibiotics were approved prior to the FDASIA in 2012. Systemic antibiotic discontinuations occurred in pharmacology classes with a large number of therapeutic alternatives, including quinolone antibacterials  and other beta-lactam antibacterials   . The FDA= 0.273) . Discont; 39.4%) .In the study period, the FDA approved 77 antibiotics for systemic use . FDA AppOut of 77 new antibiotics for systemic use approved by the FDA in the study period, 50 new antibiotics were indicated for skin and skin structure infections, 48 for urinary tract infections, and 34 were for pneumonia . Five systemic antibiotics were indicated for bacterial skin and skin structure infections, all of them due to methicillin-resistant Staphylococcus aureus (MRSA).In this study assessing FDA approvals and discontinuations of pharmaceutical products since 1980, we found an overall upward trend in the number of approvals. The therapeutic classes with the greatest number of approvals were antineoplastic, which in most recent years increased to one in three approved drugs, followed by central nervous system, alimentary tract, and metabolism drugs. These findings are consistent with the trend identified in previous studies conducted during the 2010s and over shorter timeframes ,6. We alIn the study period, antibiotics for systemic use represented the sixth therapeutic class in number of approvals but the first class in market discontinuations. The pharmacology classes with the greatest number of discontinuations were antibacterials for systemic use, diagnostic drugs, and antivirals. Almost one in five discontinuations were due to safety concerns.Congressional legislation enacted over the past 40 years to encourage the development and regulatory approval of new drugs was intended to address the need for greater effectiveness of new interventions in patients who lack effective options. The purpose of the regulations implemented to encourage the development of those new drugs was to offer improved outcomes for patients with unmet medical needs. Yet, newly developed systemic antibiotics did not provide evidence of greater efficacy relative to the drugs to which they were compared, or improved patient outcomes compared to older, less expensive generic alternatives. This is particularly the case for the QIDP designation for anti-infectives to treat serious or life-threatening diseases since the law and regulation do not require evidence of improved patient outcomes, a necessary requirement to address unmet needs for greater effectiveness. Furthermore, new antibiotics for systemic use granted the QIDP designation were evaluated for regulatory approval using non-inferiority clinical trials, and the patients enrolled in those trials had bacterial infections susceptible to already available therapeutic alternatives, thus potentially allowing for worse effectiveness compared to available therapies. This is evident in the case of antibiotics for complicated urinary tract infections (cUTI). While there were three dozen systemic antibiotics for cUTI marketed in the US, none of the six QIDP-designated antibiotics approved for cUTI demonstrated evidence of improved patient outcomes  compared to existing therapeutic options. Moreover, data derived from UTI studies is complex to interpret due to the utilization of urine cultures as a surrogate outcome whose relationship to direct patient outcomes of survival, symptoms, and patient function remains unclear. Lastly, FDASIA’s intended goal was to encourage the development of anti-infectives to treat serious or life-threatening diseases caused by resistant or potentially resistant bacteria, meaning patients who lack effective options. MRSA was the only resistant bacteria targeted by the antibiotics approved with the QIDP designation.During the past four decades, a large proportion of antibiotics have been discontinued from the US market, particularly when compared to other therapeutic areas. More specifically, market discontinuations of systemic antibiotics occurred at three times the rate of discontinuation in other drug classes. Furthermore, two in five newly approved systemic antibiotics were subsequently withdrawn from the market, and those discontinuations concentrated in pharmacological classes with a large number of therapeutic alternatives. While drug market discontinuations are correlated with the number of years after market entry, overall, drug discontinuations occurred after the market entry of therapeutic alternatives with more favorable risk–benefit trade-offs . This waAcinetobacter baumannii, CRAB) was estimated to be 20 times higher than that of colistimethate. The randomized clinical trial comparing both antibiotics showed that cefiderocol was associated with increased all-cause mortality, particularly in CRAB infections [Pharmaceutical companies may also discontinue products with low utilization due to financial considerations and market-related strategies. Prior studies found that the usage of new antibiotics was lower than anticipated due to high prices and a lack of substantial evidence from clinical trials demonstrating superior efficacy or safety ,19,20,21fections ,23. In tLastly, short-term treatment courses, compared to drugs indicated for chronic conditions, have been blamed for the marginal development of new antibiotics and the high market discontinuation rate . NeverthThis study has some limitations. The data included the first NDA for an NME. An NME or new therapeutic biologic does not necessarily add patient benefits compared to available therapies. Conversely, a new approval of a variation of an antibiotic already marketed may represent an improvement over the available alternatives if it is shown to improve patient outcomes. This study included systemic antibiotics and excluded topical antibiotics. Drug sponsor companies may not provide reasoning for market discontinuations; hence, discontinuations due to safety concerns may be underestimated. Study findings need to be interpreted in the context of regulatory changes implemented during the study period and the number of years an antibiotic has been on the market. Future research could compare the regulatory approval pathways, designations, and indications of systemic antibiotics approved by the FDA and the European Medicines Agency.Regulatory and financial incentives to accelerate the development and regulatory review of new drugs resulted in increased approvals of systemic antibiotics. The discontinuation rate of systemic antibiotics was greater than any other therapeutic class, more prevalent in pharmacological classes with a greater number of therapeutic alternatives, and not related to safety or antibacterial resistance concerns. QIDP-designated antibiotics were approved based on non-inferiority trials for indications with multiple marketed antibiotics and infections due to pathogens susceptible to currently available drugs. Over the past four decades, legislation and subsequent regulations have led to an increased availability of systemic antibiotics. However, there remains a critical need for the development of innovative therapies for patients with susceptible and resistant pathogens who lack effective options to enhance their survival, improve functioning, and reduce their burden of symptoms.


Utilization of high-quality clinical practice guidelines has the potential to positively impact health outcomes. This study aimed to assess the quality and content concordance of national and international recommendations on hypertensive disorders of pregnancy (HDPs). Searches were conducted of the MEDLINE database and reference lists generated from national and international agencies. Covidence software was used for the management of the systematic review process, the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool was used to assess guidelines for quality, and three reviewers independently screened records. The research team identified and screened a total of 399 records of which 10 were deemed high quality. Guidelines were assessed and compared regarding the treatment, prevention, and categorization of disorders. The quality of guidelines varied across different domains, with significant variation in domain scores even within individual guidelines. Not all recommendations showed a high level of methodologic rigor, and the highest-rated guidelines were from the American Heart Association, the World Health Organization, and South Africa national guidelines. Classification of hypertension differed among the guidelines, particularly in defining chronic hypertension, severe hypertension, and preeclampsia. Prevention modalities varied across guidelines, with recommendations for aspirin, calcium supplementation, and against the use of certain approaches. Treatment modalities highlighted the importance of delivery as the definitive way to terminate hypertensive disorders of pregnancy, with other management strategies provided for symptom control. The variability in guidelines and consensus statements across different contexts may reflect regional differences in healthcare practices, available resources, and research evidence. There is potential to harmonize guidelines for HDP globally while considering the unique needs of individual countries. Where guidelines may be synthesized and condensed into an accessible format, doing so could improve their use in clinical decision-making. Hypertensive disorders of pregnancy (HDPs) are disorders of high blood pressure during pregnancy that occur in women who did not have hypertension prior to pregnancy, or preeclampsia in women with hypertension prior to pregnancy. Globally, 15% of all maternal deaths were caused by hypertensive disorders in 2017 .HDPs have been classified into four categories: gestational hypertension, preeclampsia/eclampsia, chronic hypertension, and chronic hypertension with superimposed preeclampsia/eclampsia ,5. In 20Women with hypertensive disorders during pregnancy have elevated post-pregnancy risks of damage to the kidney, liver, brain and other organ systems ,9. CompaNeonatal and infant mortality risks are nearly doubled for the children of mothers with preeclampsia. However, a ‘protective’ association has also been reported for a subset of preterm or very low birth weight infants ,12,13,14Effective classification, diagnosis and management of hypertensive disorders in pregnancy are crucial to reduce the risk of morbidity and mortality for mothers and offspring. However, globally, there are discrepancies in the classification, diagnosis and management of HDPs . Policy-We initiated a comprehensive guideline content and concordance review updating and extending the findings of a previous review. Study steps comprised a comprehensive search, formulation and application of selection criteria, assessment of quality using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument , a compipregnancy, hypertension, pregnancy-induced hypertension, and hypertension in pregnancy alone and in conjunction with guidelines and guidelines as a publication type. The full search strategy is outlined in The MEDLINE database was searched for articles from 1 June 2014 to 31 December 2021, with an updated search conducted in December 2022. The starting date was selected to capture all guidelines that have been published since the previous systematic review . Terms sAll databases and websites included in the search are listed here in alphabetical order: American College of Obstetricians and Gynecologists (ACOG), American Heart Association (AHA), Australian Government Department of Health, Canadian Journal of Cardiology, Canadian Medical Association (CMA), European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) together, and ESC alone, as well as ECRI Guidelines, French Society of Hypertension (FSH), Guidelines International Network (GIN), Japanese Society of Hypertension (JSH), International Society of Hypertension (ISH), International Society for the Study of Hypertension (ISSHP), Malaysian Society of Hypertension (MSH), MEDLINE/PubMed, National Institute Health and Care Excellence Web site (NICE), NZ Ministry of Health (NZ), Pakistan Hypertension League, Philippine Society of Hypertension, Polish Societies of Hypertension, Saudi Hypertension Management Society, Scottish Intercollegiate Guidelines Network, Society of Obstetric Medicine of Australia and NZ (SOMANZ), the South African Medical Journal, Sudan Society of Hypertension (SSH), Taiwan Society of Cardiology together with the Taiwan Hypertension Society, and two separate guidelines from the World Health Organization (WHO).Records identified through MEDLINE were screened using Covidence software to organize the review process . Three rTo objectively assess guideline quality, we used the AGREE II instrument  assessedFinal domain scores (0% to 100%) were calculated based on the sum of ratings across all reviewers and scaled to include the maximum possible score as well as the difference between the maximum and minimum possible scores for that domain.Using AGREE II domain scores, guidelines were deemed high quality based on overall domain score and rank among all guidelines screened full text. Average raw scores were used to rank order and 10 highly rated guidelines were extracted.The classification of hypertension by high-quality CPGs is illustrated in Various prevention modalities were described by the CPGs, including pharmaceutical and non-pharmaceutical options.Low-dose acetylsalicylic acid use for preeclampsia prevention in high-risk women was recommended in 10 of 12 CPGs. However, dosage and timing varied among the guidelines. Dosages ranged from 75 to 162 mg depending on the CPG. Women considered high risk were those who have a personal or family history of HDPs, chronic medical disease and/or abnormal uterine artery Doppler before 24 weeks gestation. Recommendations regarding the timing of initiation of aspirin varied by CPG. Most guidelines stated therapy should be started before 16 weeks of gestation, but this recommendation ranged from between 12 to 20 weeks of gestation. Most guidelines recommended therapy continue until delivery.Five CPGs recommended calcium supplementation . Most guidelines recommended low-dose calcium supplementation for women with low dietary intake of calcium (<600 mg/day), especially among women at high risk of developing preeclampsia. Calcium dosages ranged from 1.0 g to 2.0 g/day. The SA guideline stated calcium supplementation should be given to all pregnant women, regardless of population risk factors and dietary calcium intake.Five CPGs recommend against prophylactic antioxidant therapy with vitamins C and E  due to its association with low birth weight and other adverse perinatal outcomes.Two CPGs mentioned folic acid. NZ recommended folic acid for all pregnancies to reduce the risk of spina bifida and to promote normal brain development. NICE mentioned folic acid supplementation as a means of preventing hypertensive disorders during pregnancy, without discussion of potential benefits.Two CPGs recommended against the use of low molecular weight heparin (LMWH) for HDPs (FSH and NICE).The 10 highest-ranked guidelines recommended against therapies including nitric oxide donors (France and NICE), progesterone (NICE), thiazide diuretics (NICE and WHO) and bed rest . Several CPGs did not recommend the following supplements for the prevention of hypertensive pregnancy disorders: fish oil , garlic , magnesium  and Vitamin D . Three CPGs made recommendations against dietary salt restriction .Full details of prevention modalities extracted from guidelines are outlined in Timing of birth was included in six of the highest-ranking CPGs. All guidelines recommended delivery as the only definitive way to resolve HDPs, but recommendations were provided for the management of symptoms. Delivery was recommended at ≥37 weeks gestation for women with gestational hypertension, chronic hypertension, or moderate preeclampsia. Four CPGs recommended delivery at >34 weeks for women with severe preeclampsia and adopted an expectant approach for women <34 weeks. However, this recommendation was made among all CPGs to expedite delivery in preeclamptic patients with deteriorating maternal–fetal conditions by all CPGs. Timing of birth should be based on whether the woman and baby are at risk of adverse outcomes if pregnancy is prolonged.A full description of treatment modalities recommended by CPGs is presented in Two CPGs recommended against bed rest for gestational hypertension (NICE) and for the prevention of hypertensive disorders in pregnancy (WHO). One CPG recommended against strict bed rest for improving pregnancy outcomes in women with hypertension (WHO).Methyldopa and labetalol were considered first-line treatment options by all highly-rated guidelines. Calcium antagonists, specifically nifedipine, were cited as a first-line treatment option by nine CPGs. Hydralazine was not considered a drug of choice, but it was recommended when other treatment regimens have failed to achieve adequate BP control by some guidelines . Sodium nitroprusside was considered a last resort drug treatment by two guidelines (ESC and WHO) due to prolonged treatment being associated with an increased risk of fetal cyanide poisoning. When preeclampsia was associated with pulmonary edema, nitroglycerin, given as an intravenous infusion, was recommended by one guideline (ESC).ACE inhibitors and angiotensin receptor blockers were contraindicated in pregnancy by nine of 10 CPGs (SA made no recommendation either for or against). Direct renin inhibitors were also not recommended .To reduce the risk of neonatal death, respiratory distress syndrome, cerebrovascular hemorrhage, necrotizing enterocolitis, respiratory support and intensive care unit (ICU) admission, administration of corticosteroids were recommended in cases of severe hypertension, and preeclampsia with severe features before 34 weeks .Administration of crystalloid fluid was recommended before or when administering the first IV hydralazine dose . One CPG recommended strict fluid monitoring in women with severe preeclampsia or eclampsia intrapartum and postpartum (NZ). In women with severe preeclampsia, recommendations were made to limit total fluids to 80 mL/h (NICE) or 80–85 mL/h (NZ) to reduce the risk of pulmonary oedema.Four CPGs recommended magnesium sulfate for the prevention and treatment of eclampsia as the drug of choice over other anticonvulsants . Four guidelines recommended the use of magnesium sulfate for the treatment of preeclampsia with severe features . A loading dose of 4 g was recommended intravenously over 5–15 min (NICE) and over 20 min (SA). One CPG specified 1 g/h should be administered for 24 h after the last eclamptic episode, noting recurrent episodes should be treated with a further dose of 2 to 4 g given intravenously over 5 to 15 min (NICE). If magnesium sulfate is administered for more than 5 to 7 days in pregnancy or is repeatedly used, fetal surveillance is recommended because its prolonged use has been associated with skeletal adverse effects and hypocalcemia and hypermagnesemia in neonates (NICE). One CPG-specified magnesium sulfate should not be given concomitantly with calcium channel blockers (ESC).Fetal surveillance recommendations varied among CPGs and differed in modality and frequency depending on the classification of HDPs.Early dating ultrasound , ultrasound for fetal growth , fetal heart auscultation, amniotic fluid volume and umbilical artery doppler velocimetry were all considered acceptable modalities for fetal surveillance. Cardiotocography was recommended if a cardiac anomaly was detected by two guidelines .CPG content and concordance covering the diagnostic approach and management of HDPs were assessed using the AGREE II instrument. Guidelines came from a range of countries, professional associations and international agencies. AHA guidelines scored highest using the AGREE II instrument  across aIn relation to our prior review , severalAlso in contrast to the prior review, the current review included guidelines from a wider geographic range, including highly rated guidance from sub-Saharan Africa , Asia 3, AustralOur findings stand in contrast to a review of CPGs from 2009–2019 . In the Strengths of the current study include the evaluation of each guideline by three independent raters, library scientist input, a comprehensive search strategy with the use of multiple databases and the use of a structured, validated quality rating tool. Limitations of the study were the inclusion of only English language guidelines. Due to the inability to review guidelines in other languages, this may have resulted in the exclusion of potentially relevant guidelines designed for use in non-English speaking countries. Finally, the review centered on guidelines of broader scope which may have resulted in failure to identify guidelines that, though of narrow scope, may have been pertinent to recommendations.Multiple international and national guidelines exist on the diagnosis, prevention and management of HDP. Many of these guidelines concur in their recommendations regarding the prevention and treatment of HDP, severe hypertension, preterm preeclampsia and eclampsia, and yet, there is considerable variability. The lack of clear consensus and concordance across international guidelines poses the challenge of the inaccessibility of recommendations for clinical practice.The variability in guidelines and consensus statements across different contexts may reflect regional differences in healthcare practices, available resources, and research evidence. There is potential to harmonize guidelines for HDP globally while considering the unique needs of individual countries. Where guidelines may be synthesized and condensed into an accessible format, doing so could improve their use in clinical decision-making.