Evaluating the cost-effectiveness of voclosporin for the treatment of lupus nephritis in the United States.

BACKGROUND: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus; up to 30% of patients with LN will develop end-stage kidney disease (ESKD). One of the main treatment goals for LN is preservation of kidney function, with early decreases in proteinuria associated with improved long-term outcomes. Voclosporin, a second-generation calcineurin inhibitor, was approved in the United States in 2021 for the treatment of active LN combined with background immunosuppression. The AURORA 1 study found that the use of voclosporin with low doses of mycophenolate mofetil and glucocorticoids yielded significant reductions in proteinuria. The AURORA 2 study showed long-term efficacy and safety of voclosporin over a 3-year period with kidney function preservation. The Institute for Clinical and Economic Review (ICER) is a nonprofit organization that evaluates medical evidence to help improve patient outcomes and control costs. In 2021, ICER published an economic model to estimate the impact and cost-effectiveness of LN therapies. From a US health care perspective, voclosporin was cost-effective at $149,260 per quality-adjusted life-year (QALY) and $131,528 per equal value of life-years gained (evLYG). At the time of the LN cost-effectiveness model (CEM) development, voclosporin was not yet approved in the United States and the cost of treating patients with LN with ESKD was not captured in the literature. OBJECTIVE: To evaluate the cost-effectiveness of voclosporin given the emergence of new data. METHODS: The LN CEM uses a short-term trial-based Markov model and long-term extrapolation using partitioned survival modeling data assuming adults with LN start with active disease, transitioning to complete or partial renal response, kidney failure, or death. In the current analysis, clinical data for voclosporin, duration of voclosporin treatment for nonresponders, and drug costs reflecting the 2023 price of voclosporin were updated. Additionally, health care payer costs of disease management were incorporated based on real-world claims data on the costs of treating patients with LN. RESULTS: Using the LN CEM with inputs reflecting the latest and most relevant evidence, the incremental cost of voclosporin per QALY was $88,076 and per evLYG was $77,643. For a subpopulation of Black, Hispanic, and Latino patients, the incremental cost of voclosporin per QALY was $77,435 and per evLYG was $67,828. CONCLUSIONS: Following the inclusion of updated data in the cost-effectiveness analysis, voclosporin remains a cost-effective therapy for the treatment of active LN including in a Black, Hispanic, and Latino subpopulation, substantially below the ICER willingness-to-pay threshold of $150,000/QALY.

Cochlear implant referral patterns in the UK suggest a postcode lottery with inequitable access for older adults; results of a pilot audit in five Audiology sites.

OBJECTIVE: To use a standardised reporting tool to identify potential eligible candidates for cochlear implant (CI) referral and quantify the proportion of adults who had a CI referral discussion after presenting with an audiogram within United Kingdom (UK) audiometric criteria. DESIGN: Retrospective multicentre 6-month audit of Audiology clinic databases. STUDY SAMPLE: A total of 810 adults from five geographically diverse UK Audiology sites. RESULTS: Data were collected in late 2019 after UK CI audiometric candidacy criteria changed; one site collected only 3 months of data. The proportion of potential eligible adults (based only on audiometry) considered for CI referral was 64% (521 out of 810) and varied by site (from 50% to 83%). About 24% of patients (123 out of 521) declined CI referral; this also varied across sites (12-45%). The median age of patients where CI referral was not considered was 80 years - significantly higher than the group where CI referral was considered (73 years). CONCLUSIONS: CI referral is dependent on where adults live, and how old they are. Older adults are significantly less likely to be considered for CI referral by Audiologists. Audiology clinics need more support to empower staff to talk to patients about CI referral.

Habitat alteration and fecal deposition by geese alter tundra invertebrate communities: Implications for diets of sympatric birds.

Over the last 60 years, Arctic goose populations have increased while many sympatric tundra nesting bird populations have declined. Hyperabundant geese have well-documented effects on tundra habitats, which can alter habitat use by sympatric bird species. These habitat changes may also alter invertebrate communities and abundances, with potentially important, but as of yet, undocumented effects on insectivorous birds such as shorebirds. Here, we determined the effects of goose-induced habitat alteration on invertebrate communities and relate the observed changes to shorebird diet. At sites and habitat types representing a gradient of goose influence, we identified goose-related changes in ground cover and linked these factors to variation in invertebrate communities. We then used DNA metabarcoding to characterize the diet of six shorebird species across sites and identify inter-site variation in abundance, biomass, and timing of emergence of dominant shorebird prey items. Invertebrate diversity and richness did not vary either among sites or habitat types. However, for prey items identified as part of the shorebird diet, we found significantly higher abundances and biomasses at a moderately goose-influenced site than at either low or high goose-influenced sites. Biomass of Tipulidae, the dominant prey taxon for shorebirds at the study sites, was 7.5 times higher at the moderately goose-influenced site compared to the site where goose influence was minor. We attribute this enhancement of prey biomass to both the fertilizing effect of goose fecal pellets and the moderate grazing pressure. Many studies have documented adverse effects of overabundant geese, but here we show that a moderate degree of goose grazing can lead to enhanced biomass of invertebrates, with the potential for improved shorebird foraging success and chick growth. These benefits, however, might be outweighed by negative effects of goose-induced habitat alteration and predation pressure.

Performance characteristics of five SARS-CoV-2 serological assays: Clinical utility in health-care workers.

STUDY OBJECTIVE: SARS-CoV-2, which causes coronavirus disease (COVID-19), continues to cause significant morbidity and mortality. The diagnosis of acute infection relies on reverse transcription-polymerase chain reaction (RT-PCR)-based viral detection. The objective of this study was to evaluate the optimal serological testing strategy for anti-SARS-CoV-2 antibodies which provides an important indicator of prior infection and potential short-term immunity. METHODS: The sensitivity and specificity of four different ELISA assays (Euroimmun IgG, Euroimmun NCP-IgG, Fortress and DIAsource) and one CLIA assay (Roche ELECSYS) were evaluated in 423 samples; 137 patients with confirmed RT-PCR COVID-19 infection (true positives), and 100 pre-pandemic samples collected prior to October 2019 (true negatives). A further 186 samples were collected from health-care staff and analysed by all five assays. RESULTS: The Fortress ELISA assay demonstrated the highest sensitivity and specificity followed by the Roche ECLIA assay. The highest overall sensitivity came from the assays that measured total antibody (IgM-IgG combined) and the three assays that performed the best (Fortress, Roche, Euroimmun IgG) all have different antigens as their target proteins which suggests that antigen target does not affect assay performance. In mildly symptomatic participants with either a negative RT-PCR or no RT-PCR performed, 16.76% had detectable antibodies suggesting previous infection. CONCLUSIONS: We recommend a combined testing strategy utilizing assays with different antigenic targets using the fully automated Roche ECLIA assay and confirming discordant samples with the Fortress Total Antibody ELISA assay. This study provides an important indicator of prior infection in symptomatic and asymptomatic individuals.

Behavioural responses of breeding arctic sandpipers to ground-surface temperature and primary productivity.

Most birds incubate their eggs, which requires time and energy at the expense of other activities. Birds generally have two incubation strategies: biparental where both mates cooperate in incubating eggs, and uniparental where a single parent incubates. In harsh and unpredictable environments, incubation is challenging due to high energetic demands and variable resource availability. We studied the relationships between the incubation behaviour of sandpipers (genus Calidris) and two environmental variables: temperature and a proxy of primary productivity (i.e. NDVI). We investigated how these relationships vary between incubation strategies and across species among strategies. We also studied how the relationship between current temperature and incubation behaviour varies with previous day's temperature. We monitored the incubation behaviour of nine sandpiper species using thermologgers at 15 arctic sites between 2016 and 2019. We also used thermologgers to record the ground surface temperature at conspecific nest sites and extracted NDVI values from a remote sensing product. We found no relationship between either environmental variables and biparental incubation behaviour. Conversely, as ground-surface temperature increased, uniparental species decreased total duration of recesses (TDR) and mean duration of recesses (MDR), but increased number of recesses (NR). Moreover, small species showed stronger relationships with ground-surface temperature than large species. When all uniparental species were combined, an increase in NDVI was correlated with higher mean duration, total duration and number of recesses, but relationships varied widely across species. Finally, some uniparental species showed a lag effect with a higher nest attentiveness after a warm day while more recesses occurred after a cold day than was predicted based on current temperatures. We demonstrate the complex interplay between shorebird incubation strategies, incubation behaviour, and environmental conditions. Understanding how species respond to changes in their environment during incubation helps predict their future reproductive success.

Cost-effectiveness of denosumab for the prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States.

Aims: Bone complications (also known as skeletal-related events [SREs]) pose significant health and financial burdens on patients with bone metastases. Denosumab demonstrated superiority over zoledronic acid in delaying the time to first SRE. This study examined the lifetime cost-effectiveness of denosumab vs zoledronic acid from both US payer and societal perspectives.Methods: This analysis used a lifetime Markov model and included patients with breast cancer, prostate cancer, and other solid tumors and bone metastases. The societal perspective included direct medical, direct non-medical, and indirect costs associated with denosumab and zoledronic acid; the payer perspective included direct medical costs only. Bone complication rates for each tumor type were estimated from three pivotal phase 3 studies and modified to reflect real-world incidence.Results: From a societal perspective, compared with zoledronic acid, denosumab use resulted in an incremental cost of $9,043, an incremental benefit of 0.128 quality-adjusted life-years (QALYs), a lifetime cost per QALY of $70,730, and a net monetary benefit (NMB) of $10,135 in favor of denosumab. Direct drug costs for denosumab ($28,352) were higher than zoledronic acid/untreated ($578), but were offset by reduced costs associated with bone complications. From a payer perspective, denosumab use was associated with an incremental cost of $13,396, and an incremental benefit of 0.128 QALYs, for a cost of $104,778 per QALY and an NMB of $5,782 in favor of denosumab.Limitations: Some model inputs had limited information and, given that the results may be sensitive to changes in these inputs, our findings should be interpreted within the context of the data inputs and modeling assumptions used in the analysis.Conclusions: Denosumab is a cost-effective option to prevent bone complications in patients with solid tumors when considering both payer and broader societal perspectives.

Spatio-temporal responses of predators to hyperabundant geese affect risk of predation for sympatric-nesting species.

The Arctic is undergoing rapid changes, with anthropogenic shifts in climate having important and well-documented impacts on habitat. Populations of predators and their prey are affected by changing climate and other anthropogenic factors, and these changing trophic interactions could have profound effects on breeding populations of Arctic birds. Variable abundance of lemmings (a primary prey of generalist Arctic predators) and increasing abundance of light geese (Lesser Snow and Ross' Geese; a secondary prey) could have negative consequences for numerous sympatric shorebirds (an incidental prey). Using 16 years of predator-prey observations and 13-years of shorebird nest survival data at a site near a goose colony we identify relationships among geese, lemmings, and their shared predators and then relate predator indices to shorebird risk of nest predation. During two years, we also placed time-lapse cameras and artificial shorebird nests at increasing distances from a goose colony to document spatial trends in predators and their effect on risk of predation. In the long-term data, yearly indices of light geese positively influenced indices of gulls and jaegers, and shorebird nest predation rate was negatively correlated with jaeger and fox indices. All three predator indices were highest near the goose colony and artificial nest predation probability was negatively correlated with distance from goose colony, but these effects were less apparent during the second year. Combined, these results highlight the variation in predator-mediated interactions between geese and shorebirds and outline one mechanism by which hyperabundant geese may be contributing to local or regional declines in Arctic-nesting shorebird populations.

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in four European countries: Austria, Belgium, Greece, and Italy.

Aim: The approved indication for denosumab (120 mg) was expanded in 2018 to include skeletal-related event (SRE) prevention in patients with multiple myeloma (MM). Therefore, a cost-effectiveness analysis was conducted comparing denosumab with zoledronic acid (ZA) for SRE prevention in patients with MM from the national healthcare system perspective in a representative sample of European countries: Austria, Belgium, Greece, and Italy. Methods: The XGEVA global economic model for patients with MM was used to calculate incremental cost-effectiveness ratios (ICERs) for denosumab vs ZA over a lifetime horizon. Clinical inputs were derived from the denosumab vs ZA randomized, phase 3 study ("20090482") in patients newly-diagnosed with MM, and comprised real-world adjusted SRE rates, serious adverse event (SAE) rates, treatment duration, dose intensity, progression-free survival (PFS), and overall survival (OS). Economic inputs comprised country-specific denosumab and ZA acquisition and administration costs, SRE and SAE management costs, and discount rates. Health utility decrements associated with MM disease progression, SRE and SAE occurrence, and route of administration were included. Results: Estimated ICERs (cost per quality-adjusted life-year [QALY] gained) for denosumab vs ZA in Austria, Belgium, Greece, and Italy were €26,294, €17,737, €6,982, and €27,228, respectively. Using 1-3 times gross domestic product (GDP) per capita per QALY as willingness to pay thresholds, denosumab was 69-94%, 84-96%, 79-96%, and 50-92% likely to be cost-effective vs ZA, respectively. Limitations: Economic inputs were derived from various sources, and time to event inputs were extrapolated from 20090482 study data. Conclusions: Denosumab is cost-effective vs ZA for SRE prevention in patients with MM in Austria, Belgium, Greece, and Italy, based on often-adopted World Health Organization thresholds. This conclusion is robust to changes in model parameters and assumptions. Cost-effectiveness estimates varied across the four countries, reflecting differences in healthcare costs and national economic evaluation guidelines.

A case of severe rhabdomyolysis associated with secondary adrenal insufficiency and autoimmune hepatitis.

Rhabdomyolysis is a serious and life-threatening condition which has many established causes including endocrine disturbances. Of those, thyroid, adrenal and pituitary deficiencies are the most commonly seen. Most cases of rhabdomyolysis with adrenal insufficiency that have been reported have been primary. Here, we report an encounter with a patient who presented with her second case of severe rhabdomyolysis in the setting of secondary adrenal insufficiency. The cause for corticotropic suppression was most likely autoimmune hypophysitis given the presence of other autoimmune comorbidities including a new diagnosis of autoimmune hepatitis. In addition to her case, we present a brief review of the literature pertaining to cases of rhabdomyolysis attributed to adrenal insufficiency.

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America.

OBJECTIVE: A large, pivotal, phase 3 trial in patients with newly diagnosed multiple myeloma (MM) demonstrated that denosumab, compared with zoledronic acid, was non-inferior for the prevention of skeletal-related events (SREs), extended the observed median progression-free survival (PFS) by 10.7 months, and showed significantly less renal toxicity. The cost-effectiveness of denosumab vs zoledronic acid in MM in the US was assessed from societal and payer perspectives. METHODS: The XGEVA Global Economic Model was developed by integrating data from the phase 3 trial comparing the efficacy of denosumab with zoledronic acid for the prevention of SREs in MM. SRE rates were adjusted to reflect the real-world incidence. The model included utility decrements for SREs, administration, serious adverse events (SAEs), and disease progression. Drug, administration, SRE management, SAEs, and anti-MM treatment costs were based on data from published studies. For the societal perspective, the model additionally included SRE-related direct non-medical costs and indirect costs. The net monetary benefit (NMB) was calculated using a willingness-to-pay threshold of US$150,000. One-way deterministic and probabilistic sensitivity analyses were conducted. RESULTS: From a societal perspective, compared with zoledronic acid, the use of denosumab resulted in an incremental cost of US$26,329 and an incremental quality-adjusted life-year (QALY) of 0.2439, translating into a cost per QALY gained of US$107,939 and a NMB of US$10,259 in favor of denosumab. Results were sensitive to SRE rates and PFS parameters. LIMITATIONS: Costs were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters. PFS and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. CONCLUSION: Denosumab's efficacy in delaying or preventing SREs, potential to improve PFS, and lack of renal toxicity make it a cost-effective option for the prevention of SREs in MM compared with zoledronic acid.

Light oiling of feathers increases flight energy expenditure in a migratory shorebird.

Flying birds depend on their feathers to undertake most activities, and maintain them in peak condition through periodic molt and frequent preening. Even small exposures to crude oil reduce the integrity of feathers, and could impair flight performance. We trained wild western sandpipers (Calidris mauri) to perform endurance flights in a wind tunnel, and used magnetic resonance body composition analysis to measure energy expenditure after birds were exposed to weathered MC252 crude oil from the Deepwater Horizon oil spill. The cost of transport was 0.26±0.04 kJ km-1 in controls, and increased by 22% when the trailing edges of the wing and tail were oiled (<20% of body surface; considered light oiling). Additional crude oil on breast and back feathers (∼30% total surface; moderate oiling) increased the cost of transport by 45% above controls. Oiling tended to decrease flight control, and only half of moderately oiled birds completed the flight test. We then flew birds at a range of speeds to estimate basic kinematic parameters. At low speeds, light and moderately oiled birds had larger wingbeat amplitudes than controls, while moderately oiled birds showed greater wingbeat frequencies across all speeds, and a shift in optimal flight speed towards higher wind speeds. We suggest these changes reflect poorer lift production and increased drag on the wings and body. Oiling will increase the difficulty and energy costs of locomotion for daily and seasonal activities such as foraging, predator evasion, territory defense, courtship, chick provisioning, commuting and long-distance migration. These sub-lethal effects must be considered in oil spill impact assessments.

Reprint of: Trouble on takeoff: Crude oil on feathers reduces escape performance of shorebirds.

The ability to takeoff quickly and accelerate away from predators is crucial to bird survival. Crude oil can disrupt the fine structure and function of feathers, and here we tested for the first time how small amounts of oil on the trailing edges of the wings and tail of Western sandpipers (Calidris mauri) affected takeoff flight performance. In oiled birds, the distance travelled during the first 0.4s after takeoff was reduced by 29%, and takeoff angle was decreased by 10° compared to unoiled birds. Three-axis accelerometry indicated that oiled sandpipers produced less mechanical power output per wingbeat during the initial phase of flight. Slower and lower takeoff would make oiled birds more likely to be targeted and captured by predators, reducing survival and facilitating the exposure of predators to oil. Whereas the direct mortality of heavily-oiled birds is often obvious and can be quantified, our results show that there are significant sub-lethal effects of small amounts crude oil on feathers, which must be considered in natural resource injury assessments for birds.

Toxicological and thermoregulatory effects of feather contamination with artificially weathered MC 252 oil in western sandpipers (Calidris mauri).

The external contamination of bird feathers with crude oil might have effects on feather structure and thus on thermoregulation. We tested the thermoregulatory ability of western sandpipers (Calidris mauri) in a respirometry chamber with oil applied either immediately prior, or three days before the experiment. The birds were then exposed to a sliding cold temperature challenge between 27°C and -3°C to calculate thermal conductance. After the experiment, a large blood sample was taken and the liver extracted to measure a range of parameters linked to toxicology and oxidative stress. No differences in thermal conductance were observed among groups, but birds exposed to oil for three days had reduced body temperatures and lost more body mass during that period. At necropsy, oiled birds showed a decrease in plasma albumin and sodium, and an increase in urea. This is reflective of dysfunction in the kidney at the loop of Henle. Birds, especially when exposed to the oil for three days, showed signs of oxidative stress and oxidative damage. These results show that the ingestion of externally applied oil through preening or drinking can cause toxic effects even in low doses, while we did not detect a direct effect of the external oil on thermoregulation over the temperature range tested.

Effect of oral exposure to artificially weathered Deepwater Horizon crude oil on blood chemistries, hepatic antioxidant enzyme activities, organ weights and histopathology in western sandpipers (Calidris mauri).

Shorebirds were among birds exposed to Mississippi Canyon 252 (MC252) crude oil during the 2010 Deep Water Horizon (DWH) oil spill in the Gulf of Mexico. The western sandpiper (Calidris mauri) was chosen as one of four species for initial oral dosing studies conducted under Phase 2 of the avian toxicity studies for the DWH Natural Resource Damage Assessment (NRDA). Thirty western sandpipers were assigned to one of three treatment groups, 10 birds per group. The control group was sham gavaged and the treatment groups were gavaged with 1 or 5mL oil kg bw-1 daily for 20 days. Periodic blood samples for hemoglobin measurements were collected during the trial. A final blood sample used to determine hemoglobin concentration in addition to complete blood counts, plasma clinical chemistries, haptoglobin concentration and plasma electrophoresis was collected when birds were euthanized and necropsied on day 21. Tissues were removed, weighed and processed for subsequent histopathological evaluation. There were numerical decreases in hemoglobin concentrations in oil-dosed birds over the 21-day trial, but values were not significantly different compared to controls on day 21. There were no significant differences between controls and oiled birds in complete blood counts, plasma chemistries, haptoglobin concentration, and plasma electrophoresis endpoints. Of the hepatic oxidative stress endpoints assessed, the total antioxidant capacity assessment (Trolox equivalents) for the control group was lower compared to the 1mL oil kg bw-1 group. Absolute liver weights in the 5mL oil kg bw-1 group were significantly greater compared to controls. While not conclusive, the numerical decrease in hemoglobin concentration and significant increase in absolute liver weight are consistent with exposure to oil. Histological changes in the adrenal gland could be considered a non-specific indicator of stress resulting from exposure to oil. It is possible that the quantity of oil absorbed was not sufficient to induce clearly evident hemolytic anemia or that the western sandpiper is relatively insensitive to ingested oil.

Trouble on takeoff: Crude oil on feathers reduces escape performance of shorebirds.

The ability to takeoff quickly and accelerate away from predators is crucial to bird survival. Crude oil can disrupt the fine structure and function of feathers, and here we tested for the first time how small amounts of oil on the trailing edges of the wings and tail of Western sandpipers (Calidris mauri) affected takeoff flight performance. In oiled birds, the distance travelled during the first 0.4s after takeoff was reduced by 29%, and takeoff angle was decreased by 10° compared to unoiled birds. Three-axis accelerometry indicated that oiled sandpipers produced less mechanical power output per wingbeat during the initial phase of flight. Slower and lower takeoff would make oiled birds more likely to be targeted and captured by predators, reducing survival and facilitating the exposure of predators to oil. Whereas the direct mortality of heavily-oiled birds is often obvious and can be quantified, our results show that there are significant sub-lethal effects of small amounts crude oil on feathers, which must be considered in natural resource injury assessments for birds.

Correction: Long Term Population, City Size and Climate Trends in the Fertile Crescent: A First Approximation.

[This corrects the article DOI: 10.1371/journal.pone.0152563.].

The evaluation of 3 diets for rearing Hyalella azteca and the influence of diet on acute ammonia toxicity.

Three Hyalella azteca cultures were reared on different diets since birth, reflecting the recommended diets of various investigators. The 3 diets consisted of fish flakes (FF), a mixture of fish flakes supplemented with the diatom Thalassiosira weissflogii (FF-D), and a mixture of fish flakes supplemented with yeast, cereal grass media, and trout chow (FF-YCT). The 3 diets were evaluated by comparing 20 wk of culturing data, along with the organism's response to standard 96-h toxicity testing with ammonium chloride over a range of pH and temperature. Hyalella azteca fed the FF-D diet had the highest overall survival rate (96.6%, standard deviation [SD] 4.3%) compared to those fed the FF diet (92.0%, SD 12.7%), or the FF-YCT diet (91.1%, SD 14.8%), although difference in survival was not statistically significant. Organisms fed the FF-D diet produced a higher number of young per week per adult (6.1, SD 2.8) than the FF diet (5.1, SD 2.2), or the FF-YCT diet (4.0, SD 1.2), although differences were not statistically significant. Of the diets evaluated, H. azteca reared on the FF-D diet were often significantly more resistant to total and un-ionized ammonia toxicity in acute 96-h testing than those reared on the other 2 diets across the 2 temperatures and 5 pHs tested, suggesting this may be the most optimal diet for this species. Environ Toxicol Chem 2016;35:2416-2424. © 2016 SETAC.

Long Term Population, City Size and Climate Trends in the Fertile Crescent: A First Approximation.

Over the last 8000 years the Fertile Crescent of the Near East has seen the emergence of urban agglomerations, small scale polities and large territorial empires, all of which had profound effects on settlement patterns. Computational approaches, including the use of remote sensing data, allow us to analyse these changes at unprecedented geographical and temporal scales. Here we employ these techniques to examine and compare long term trends in urbanisation, population and climate records. Maximum city size is used as a proxy for the intensity of urbanisation, whilst population trends are modelled from settlement densities in nine archaeological surveys conducted over the last 30 years across the region. These two measures are then compared with atmospheric moisture levels derived from multiple proxy analyses from two locations close to the study area, Soreq Cave in Israel and Lake Van in south-eastern Turkey, as well as wider literature. The earliest urban sites emerged during a period of relatively high atmospheric moisture levels and conform to a series of size thresholds. However, after the Early Bronze Age maximum urban size and population levels increase rapidly whilst atmospheric moisture declines. We argue that although the initial phase of urbanization may have been linked to climate conditions, we can see a definitive decoupling of climate and settlement patterns after 2000 BC. We relate this phenomenon to changes in socio-economic organisation and integration in large territorial empires. The complex relationships sustaining urban growth during this later period resulted in an increase in system fragility and ultimately impacted on the sustainability of cities in the long term.